NOVA2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0003729 mRNA binding	IBA GO_REF:0000033	ACCEPT	Summary: NOVA2 binds pre-mRNA through its KH domains to regulate alternative splicing. The IBA annotation is well-supported by phylogenetic evidence and extensive experimental data from the NOVA family showing direct mRNA binding (PMID:10811881, PMID:32197073). Reason: NOVA2 is a well-characterized mRNA-binding protein. This is a core molecular function supported by structural studies showing KH domain-RNA interactions and functional studies demonstrating direct binding to pre-mRNA targets. The phylogenetic inference is consistent with extensive experimental evidence. Supporting Evidence: PMID:10811881 The Nova family of proteins are target antigens in the autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia and contain K-homology (KH)-type RNA binding domains. PMID:32197073 The NOVA2 variant protein shows decreased ability to bind target RNA sequences file:human/NOVA2/NOVA2-deep-research-falcon.md model: Edison Scientific Literature
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: NOVA2 localizes to the nucleus where it regulates co-transcriptional alternative splicing. UniProt annotation and deep research reviews confirm nuclear localization as the primary site of NOVA2 function. Reason: Nuclear localization is essential for NOVA2's role in regulating alternative splicing of pre-mRNA. The protein contains a bipartite nuclear localization signal (residues 10-26 per UniProt). This is a core cellular component annotation consistent with its molecular function. Supporting Evidence: UniProt:Q9UNW9 SUBCELLULAR LOCATION: Nucleus
GO:0005737 cytoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Some evidence suggests NOVA proteins may have cytoplasmic roles for specific targets, particularly in 3'UTR binding and alternative polyadenylation. However, the primary site of function is nuclear. Reason: While NOVA2's primary function occurs in the nucleus for co-transcriptional splicing regulation, there is evidence from deep research that NOVA proteins can bind 3'UTRs and localize with target mRNAs in neuronal compartments, suggesting some cytoplasmic presence. This is a secondary localization rather than the primary site of function. Supporting Evidence: file:human/NOVA2/NOVA2-deep-research-falcon.md Evidence also supports binding to 3'UTRs and localization with target mRNAs in neuronal compartments, indicating functions that can extend to cytoplasmic RNA regulation for specific transcripts
GO:0000381 regulation of alternative mRNA splicing, via spliceosome	IBA GO_REF:0000033	ACCEPT	Summary: This is the core biological process function of NOVA2. It regulates alternative splicing with position-dependent rules - binding upstream promotes exon skipping, binding downstream promotes inclusion. Approximately 700 targets identified in brain (PMID:32197073 and deep research reviews). Reason: Regulation of alternative splicing is the primary biological function of NOVA2. This is extensively documented in the literature and is the central function that explains all downstream biological effects (neuronal development, axon guidance, thermogenesis regulation). The IBA annotation correctly captures this core function. Supporting Evidence: PMID:32197073 The neuro-oncological ventral antigen 2 (NOVA2) protein is a major factor regulating neuron-specific alternative splicing (AS) PMID:10811881 The Nova-1 protein has recently been shown to regulate alternative splicing of the alpha2 glycine receptor subunit pre-mRNA by binding to an intronic element containing repeats of the tetranucleotide UCAU
GO:0000398 mRNA splicing, via spliceosome	IBA GO_REF:0000033	ACCEPT	Summary: NOVA2 is involved in mRNA splicing as a regulatory factor, not a core spliceosome component. This term is broader than GO:0000381 (regulation of alternative mRNA splicing). While not incorrect, the more specific term better captures NOVA2's function. Reason: This is a valid broader annotation. NOVA2 participates in the splicing process by regulating exon inclusion/exclusion through modulating spliceosome assembly. The UniProt function annotation states it "blocking U1 snRNP binding and exon inclusion, whereas binding to an intronic 5'-YCAY-3' cluster enhances spliceosome assembly and exon inclusion." Both this and the more specific GO:0000381 are appropriate. Supporting Evidence: UniProt:Q9UNW9 Binding to an exonic 5'-YCAY-3' cluster changes the protein complexes assembled on pre-mRNA, blocking U1 snRNP binding and exon inclusion, whereas binding to an intronic 5'- YCAY-3' cluster enhances spliceosome assembly and exon inclusion.
GO:0003676 nucleic acid binding	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: This IEA annotation from InterPro KH domain mapping is overly general. NOVA2 specifically binds RNA (mRNA/pre-mRNA), not DNA. More specific terms are available and annotated. Reason: While technically not incorrect (RNA is a nucleic acid), this term is too general for NOVA2. The protein specifically binds RNA through its KH domains, and more informative annotations exist (GO:0003723 RNA binding, GO:0003729 mRNA binding, GO:1990825 sequence-specific mRNA binding). This IEA annotation adds no value beyond what is captured by the more specific terms. Proposed replacements: RNA binding sequence-specific mRNA binding
GO:0003723 RNA binding	IEA GO_REF:0000120	ACCEPT	Summary: RNA binding is a core molecular function of NOVA2. This IEA annotation is supported by multiple other evidence types including IDA (PMID:32197073), HDA (PMID:22681889), and NAS (PMID:10735272). Reason: This annotation is correct and well-supported. NOVA2 is definitively an RNA-binding protein with KH domains that bind YCAY motifs in RNA. Multiple experimental evidence codes support this annotation. Supporting Evidence: PMID:10735272 Screening of a human brain cDNA library with this exon identified a 1.9 kb cDNA with extensive homology to NOVA1, including three nearly identical KH domains characteristic of a subtype of RNA-binding proteins.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Duplicate annotation of nuclear localization from UniProt subcellular location vocabulary mapping. This is consistent with the IBA annotation for the same term. Reason: Nuclear localization is well-established for NOVA2. This IEA annotation from UniProt keyword mapping is consistent with the IBA annotation and the protein's function in nuclear pre-mRNA splicing regulation. Supporting Evidence: UniProt:Q9UNW9 SUBCELLULAR LOCATION: Nucleus
GO:0006397 mRNA processing	IEA GO_REF:0000043	ACCEPT	Summary: mRNA processing is a broad parent term that encompasses splicing. NOVA2 regulates alternative splicing, a specific form of mRNA processing. This annotation is correct but less informative than more specific terms. Reason: This is a valid broader annotation. NOVA2 participates in mRNA processing through its role in alternative splicing regulation. The IEA from UniProt keyword mapping is appropriate, though more specific splicing terms are also annotated. Supporting Evidence: UniProt:Q9UNW9 Functions to regulate alternative splicing in neurons by binding pre-mRNA in a sequence-specific manner to activate exon inclusion or exclusion
GO:0007399 nervous system development	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: NOVA2 plays critical roles in nervous system development through its splicing regulation of neuronal genes. However, this is a downstream pleiotropic effect rather than the core molecular function. Mutations cause NEDASB neurodevelopmental disorder (PMID:32197073). Reason: While NOVA2 clearly impacts nervous system development (evidenced by NEDASB disease caused by NOVA2 mutations), this is a downstream biological outcome of its core function in regulating alternative splicing. The term captures an important phenotypic consequence but not the primary molecular role. Supporting Evidence: PMID:32197073 We report here six individuals with de novo frameshift variants in NOVA2 affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features
GO:0008380 RNA splicing	IEA GO_REF:0000043	ACCEPT	Summary: RNA splicing is the broader process that encompasses NOVA2's function in alternative splicing regulation. This annotation from UniProt keyword mapping is correct. Reason: NOVA2 is involved in RNA splicing as a regulatory factor. This broader term encompasses the more specific GO:0000381 (regulation of alternative mRNA splicing, via spliceosome). Both annotations are appropriate. Supporting Evidence: UniProt:Q9UNW9 regulates splicing in only a subset of regulated exons
GO:1990825 sequence-specific mRNA binding	IEA GO_REF:0000117	ACCEPT	Summary: This is the most specific and accurate molecular function term for NOVA2. It recognizes YCAY (UCAY) tetranucleotide motifs in pre-mRNA through its KH3 domain. IDA evidence from PMID:10811881 directly supports this annotation. Reason: This term precisely captures NOVA2's molecular function. The protein binds RNA in a sequence-specific manner, recognizing YCAY motifs. This is experimentally demonstrated and represents the core molecular activity. The ARBA machine learning annotation is consistent with experimental evidence. Supporting Evidence: PMID:10811881 we have used selection-amplification to demonstrate that the KH3 domain of Nova recognizes a single UCAY element in the context of a 20-base hairpin RNA
GO:0000381 regulation of alternative mRNA splicing, via spliceosome	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate annotation from Ensembl Compara orthology transfer. This core function annotation is consistent with IBA, ISS, and IMP evidence for the same term. Reason: This IEA annotation from Ensembl orthology is consistent with multiple other evidence sources. Regulation of alternative splicing is NOVA2's core biological function. Supporting Evidence: PMID:32197073 The neuro-oncological ventral antigen 2 (NOVA2) protein is a major factor regulating neuron-specific alternative splicing (AS)
GO:0003729 mRNA binding	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate annotation of mRNA binding from Ensembl Compara. Consistent with IBA and ISS evidence. Reason: mRNA binding is a core molecular function of NOVA2. This IEA is consistent with other evidence types. Supporting Evidence: PMID:10811881 The Nova family of proteins are target antigens in the autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia and contain K-homology (KH)-type RNA binding domains.
GO:0021954 central nervous system neuron development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOVA2 regulates splicing of axon guidance genes during cortical development. This is supported by ISS evidence and mouse knockout studies. UniProt notes NOVA2 "uniquely regulates alternative splicing events of a series of axon guidance related genes during cortical development." Reason: This annotation captures an important developmental role of NOVA2 in the CNS, but it represents a downstream biological consequence of the core splicing regulatory function rather than the primary molecular activity. The annotation is valid but represents a pleiotropic effect. Supporting Evidence: UniProt:Q9UNW9 Uniquely regulates alternative splicing events of a series of axon guidance related genes during cortical development, being essential for central nervous system development by regulating neural networks wiring.
GO:0120163 negative regulation of cold-induced thermogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOVA proteins suppress adipose tissue thermogenesis through alternative splicing regulation. This was demonstrated in mouse adipocytes (PMID:27635635). NOVA2 is expressed in human adipose tissue and likely contributes to this function. Reason: This represents a tissue-specific function of NOVA proteins in adipose tissue, distinct from the primary neuronal role. The annotation is valid based on mouse studies showing NOVA-deficient adipocytes have increased thermogenesis. However, this is a non-core function outside the nervous system. Supporting Evidence: PMID:27635635 Phenotypic analysis of the NOVA-deficient mice demonstrated increased adipose tissue thermogenesis and improved glycemia. We show that NOVA proteins mediate a splicing program that suppresses adipose tissue thermogenesis.
GO:1902667 regulation of axon guidance	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOVA2 regulates splicing of axon guidance genes. Mouse studies and zebrafish rescue experiments (PMID:32197073) demonstrate this function. UniProt notes unique regulation of axon guidance gene splicing. Reason: This annotation captures an important developmental role where NOVA2 regulates splicing of axon guidance genes. While biologically significant, this is a downstream effect of the core splicing regulatory function rather than the primary molecular activity. Supporting Evidence: PMID:32197073 It also fails to complement the effect on neurite outgrowth induced by NOVA2 downregulation in vitro and to rescue alterations of retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. UniProt:Q9UNW9 Uniquely regulates alternative splicing events of a series of axon guidance related genes during cortical development
GO:0021954 central nervous system neuron development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse ortholog (UniProtKB:A0A1W2P872). Consistent with IEA annotation and supported by UniProt functional description. Reason: Valid annotation based on sequence similarity to mouse Nova2. This developmental role is well-established but represents a downstream biological consequence of splicing regulation rather than core function. Supporting Evidence: UniProt:Q9UNW9 being essential for central nervous system development by regulating neural networks wiring
GO:1902667 regulation of axon guidance	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse ortholog. Consistent with IEA annotation and experimental evidence from zebrafish rescue studies (PMID:32197073). Reason: Valid annotation based on sequence similarity. Regulation of axon guidance through splicing of target genes is a well-documented NOVA2 function but represents a downstream biological process. Supporting Evidence: PMID:32197073 to rescue alterations of retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish
GO:1990825 sequence-specific mRNA binding	IDA PMID:10811881 The tetranucleotide UCAY directs the specific recognition of...	ACCEPT	Summary: Direct experimental evidence from selection-amplification studies demonstrating that the Nova KH3 domain recognizes UCAY tetranucleotide motifs in RNA. This is the definitive evidence for NOVA2's molecular function. Reason: This is the highest-quality evidence for NOVA2's core molecular function. The Jensen et al. study directly demonstrated sequence-specific RNA recognition by the KH3 domain using biochemical selection experiments. This annotation should be retained as it precisely captures the molecular activity. Supporting Evidence: PMID:10811881 we have used selection-amplification to demonstrate that the KH3 domain of Nova recognizes a single UCAY element in the context of a 20-base hairpin RNA; the UCAY tetranucleotide is optimally presented as a loop element of the hairpin scaffold
GO:0000381 regulation of alternative mRNA splicing, via spliceosome	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse ortholog. This core function is also supported by IBA, IMP, and IEA evidence. Consistent with extensive experimental literature. Reason: Valid ISS annotation for this core biological function. The annotation is consistent with multiple other evidence types and extensive experimental documentation of NOVA2's role in splicing regulation. Supporting Evidence: PMID:32197073 a major factor regulating neuron-specific alternative splicing (AS)
GO:0000381 regulation of alternative mRNA splicing, via spliceosome	IMP PMID:32197073 De Novo Frameshift Variants in the Neuronal Splicing Factor ...	ACCEPT	Summary: Direct experimental evidence from NOVA2 knockdown studies showing 41 genes differentially spliced, and demonstration that variant NOVA2 proteins show decreased splicing regulation ability. Reason: High-quality IMP evidence from human neural cell studies. The Mattioli et al. study demonstrated splicing changes upon NOVA2 downregulation and showed that disease-causing variants have impaired splicing regulatory activity. This directly supports the annotation. Supporting Evidence: PMID:32197073 We detected 41 genes differentially spliced after NOVA2 downregulation in human neural cells. The NOVA2 variant protein shows decreased ability to bind target RNA sequences and to regulate target AS events.
GO:0003723 RNA binding	IDA PMID:32197073 De Novo Frameshift Variants in the Neuronal Splicing Factor ...	ACCEPT	Summary: Direct experimental evidence showing NOVA2 binds RNA and that disease variants have decreased RNA binding ability. Reason: Valid IDA evidence from functional studies of NOVA2 variants. The study demonstrated that wild-type NOVA2 binds target RNA sequences, while pathogenic variants show decreased binding ability. Supporting Evidence: PMID:32197073 The NOVA2 variant protein shows decreased ability to bind target RNA sequences
GO:0003729 mRNA binding	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse ortholog. Consistent with IBA and IEA evidence for this core molecular function. Reason: Valid ISS annotation for mRNA binding. NOVA2's function as an mRNA-binding protein is well-established and this annotation is consistent with multiple other evidence types. Supporting Evidence: PMID:10811881 The Nova family of proteins... contain K-homology (KH)-type RNA binding domains
GO:0030182 neuron differentiation	IMP PMID:32197073 De Novo Frameshift Variants in the Neuronal Splicing Factor ...	KEEP AS NON CORE	Summary: Evidence from NOVA2 knockdown showing effects on neurite outgrowth, and from human patients with NOVA2 mutations showing neurodevelopmental defects including structural brain abnormalities. Reason: Valid IMP evidence from functional studies. The study showed NOVA2 downregulation affects neurite outgrowth in vitro and causes neurodevelopmental disorder in humans. However, this represents a downstream biological outcome of splicing dysregulation rather than the core molecular function. Supporting Evidence: PMID:32197073 It also fails to complement the effect on neurite outgrowth induced by NOVA2 downregulation in vitro
GO:0051252 regulation of RNA metabolic process	IMP PMID:32197073 De Novo Frameshift Variants in the Neuronal Splicing Factor ...	MARK AS OVER ANNOTATED	Summary: NOVA2 regulates RNA metabolism through alternative splicing. This term is very broad and less informative than more specific splicing terms that are also annotated. Reason: While technically correct (alternative splicing regulation is a form of RNA metabolism regulation), this term is overly broad and less informative than GO:0000381 (regulation of alternative mRNA splicing, via spliceosome) which is also annotated with IMP evidence from the same publication. The more specific term should be preferred. Proposed replacements: regulation of alternative mRNA splicing, via spliceosome Supporting Evidence: PMID:32197073 Epub 2020 Mar 19. De Novo Frameshift Variants in the Neuronal Splicing Factor NOVA2 Result in a Common C-Terminal Extension and Cause a Severe Form of Neurodevelopmental Disorder.
GO:0120163 negative regulation of cold-induced thermogenesis	ISS PMID:27635635 An alternative splicing program promotes adipose tissue ther...	KEEP AS NON CORE	Summary: Based on mouse studies showing NOVA-deficient adipocytes have increased thermogenesis. NOVA proteins suppress adipose tissue thermogenesis through splicing regulation. Human NOVA2 is expressed in adipose. Reason: Valid annotation based on mouse studies. The Vernia et al. study demonstrated that NOVA proteins suppress thermogenesis in adipose tissue through alternative splicing programs. While NOVA2 expression is documented in human adipose tissue, this represents a tissue-specific non-neuronal function. Supporting Evidence: PMID:27635635 NOVA proteins mediate a splicing program that suppresses adipose tissue thermogenesis file:human/NOVA2/NOVA2-deep-research-falcon.md NOVA1 and NOVA2 mRNA expression in abdominal subcutaneous adipose of obese and non-obese matched humans was examined
GO:0003723 RNA binding	HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ...	ACCEPT	Summary: High-throughput data from mRNA-bound proteome study identifying NOVA2 as an RNA-binding protein. The Baltz et al. study used UV crosslinking and mass spectrometry to identify mRNA-bound proteins. Reason: Valid HDA evidence from a well-conducted proteomics study. The identification of NOVA2 in the mRNA-bound proteome is consistent with its known function as an RNA-binding protein. While high-throughput, this provides independent support for the annotation. Supporting Evidence: PMID:22681889 We developed a photoreactive nucleotide-enhanced UV crosslinking and oligo(dT) purification approach to identify the mRNA-bound proteome using quantitative proteomics
GO:0003723 RNA binding	NAS PMID:10735272 ANOVA, a putative astrocytic RNA-binding protein gene that m...	ACCEPT	Summary: Original cloning paper describing NOVA2 (ANOVA) as an RNA-binding protein based on sequence homology to NOVA1 and presence of KH domains. Reason: Valid NAS evidence from the original gene identification paper. The presence of three KH domains characteristic of RNA-binding proteins was noted, providing the initial basis for predicting RNA binding function. This has been subsequently confirmed by direct experimental evidence. Supporting Evidence: PMID:10735272 Screening of a human brain cDNA library with this exon identified a 1.9 kb cDNA with extensive homology to NOVA1, including three nearly identical KH domains characteristic of a subtype of RNA-binding proteins.

Core Functions

Sequence-specific mRNA binding activity via KH domains recognizing YCAY tetranucleotide motifs in pre-mRNA, functioning in the nucleus to regulate alternative splicing

Molecular Function:

sequence-specific mRNA binding

Directly Involved In:

regulation of alternative mRNA splicing, via spliceosome

Cellular Locations:

nucleus

Supporting Evidence:

PMID:10811881
we have used selection-amplification to demonstrate that the KH3 domain of Nova recognizes a single UCAY element in the context of a 20-base hairpin RNA
PMID:32197073
The NOVA2 variant protein shows decreased ability to bind target RNA sequences and to regulate target AS events.

Regulation of neuronal alternative splicing programs affecting axon guidance genes during central nervous system development; mutations cause neurodevelopmental disorder NEDASB

Molecular Function:

sequence-specific mRNA binding

Directly Involved In:

central nervous system neuron development regulation of axon guidance

Cellular Locations:

nucleus

Supporting Evidence:

PMID:32197073
Uniquely regulates alternative splicing events of a series of axon guidance related genes during cortical development, being essential for central nervous system development by regulating neural networks wiring.
UniProt:Q9UNW9
mutations cause NEDASB neurodevelopmental disorder

Regulation of alternative splicing in adipocytes, suppressing thermogenic gene expression programs; expressed in white adipose tissue where it functions redundantly with NOVA1

Molecular Function:

mRNA binding

Directly Involved In:

negative regulation of cold-induced thermogenesis

Cellular Locations:

nucleus

Supporting Evidence:

PMID:27635635
NOVA proteins mediate a splicing program that suppresses adipose tissue thermogenesis

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10735272

ANOVA, a putative astrocytic RNA-binding protein gene that maps to chromosome 19q13.3.

NOVA2 contains three KH domains characteristic of RNA-binding proteins

"Screening of a human brain cDNA library with this exon identified a 1.9 kb cDNA with extensive homology to NOVA1, including three nearly identical KH domains characteristic of a subtype of RNA-binding proteins."
NOVA2 expression is restricted to brain tissue

"Northern blots demonstrated expression of a 2.5 kb mRNA in brain, but in no other tissues."

PMID:10811881

The tetranucleotide UCAY directs the specific recognition of RNA by the Nova K-homology 3 domain.

The Nova KH3 domain recognizes UCAY tetranucleotide motifs in RNA with sequence specificity

"we have used selection-amplification to demonstrate that the KH3 domain of Nova recognizes a single UCAY element in the context of a 20-base hairpin RNA"
The UCAY binding motif is optimally presented as a loop element within RNA secondary structure

"the UCAY tetranucleotide is optimally presented as a loop element of the hairpin scaffold and requires protein residues C-terminal to the previously defined KH domain"
Nova proteins regulate alternative splicing by binding intronic UCAU repeats

"The Nova-1 protein has recently been shown to regulate alternative splicing of the alpha2 glycine receptor subunit pre-mRNA by binding to an intronic element containing repeats of the tetranucleotide UCAU."

PMID:22681889

The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.

NOVA2 was identified as part of the mRNA-bound proteome in human cells

"We developed a photoreactive nucleotide-enhanced UV crosslinking and oligo(dT) purification approach to identify the mRNA-bound proteome using quantitative proteomics"

PMID:27635635

An alternative splicing program promotes adipose tissue thermogenesis.

NOVA splicing factors suppress adipose tissue thermogenesis through alternative splicing

"Phenotypic analysis of the NOVA-deficient mice demonstrated increased adipose tissue thermogenesis and improved glycemia. We show that NOVA proteins mediate a splicing program that suppresses adipose tissue thermogenesis."
Both NOVA1 and NOVA2 proteins are expressed in white adipocytes but not hepatocytes

"NOVA proteins were not detected in liver, but both NOVA1 and NOVA2 proteins were found in white adipocytes"
NOVA gene expression is reduced in adipocytes of obese mice and humans

"Interestingly, Nova gene expression in white adipocytes was partially reduced in obese humans and mice"
NOVA1 and NOVA2 show functional redundancy in adipocyte alternative splicing

"However, the effect of compound NOVA1 plus NOVA2 deficiency to cause widespread changes in alternative pre-mRNA splicing ... indicates that these NOVA proteins exhibit some functional redundancy in adipocytes."

PMID:32197073

De Novo Frameshift Variants in the Neuronal Splicing Factor NOVA2 Result in a Common C-Terminal Extension and Cause a Severe Form of Neurodevelopmental Disorder.

NOVA2 is a major regulator of neuron-specific alternative splicing

"The neuro-oncological ventral antigen 2 (NOVA2) protein is a major factor regulating neuron-specific alternative splicing (AS)"
De novo frameshift variants in NOVA2 cause a severe neurodevelopmental disorder (NEDASB)

"We report here six individuals with de novo frameshift variants in NOVA2 affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait, and abnormal brain MRI."
NOVA2 downregulation affects splicing of 41 genes in human neural cells

"We detected 41 genes differentially spliced after NOVA2 downregulation in human neural cells."
NOVA2 disease variants show decreased RNA binding and splicing regulatory activity

"The NOVA2 variant protein shows decreased ability to bind target RNA sequences and to regulate target AS events."
NOVA2 is required for neurite outgrowth and axonal pathfinding

"It also fails to complement the effect on neurite outgrowth induced by NOVA2 downregulation in vitro and to rescue alterations of retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish."

file:human/NOVA2/NOVA2-deep-research-falcon.md

Deep research report on NOVA2

Deep Research

Falcon

(NOVA2-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 10 citations 2026-01-13T19:41:58.123474

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive research report: NOVA2 (UniProt Q9UNW9)

Gene/protein verification and identity
- Symbol and organism: NOVA2 encodes the human RNA-binding protein Nova-2, a member of the neuronal NOVA family originally identified as a paraneoplastic autoantigen and subsequently recognized as a key splicing regulator in neurons and endothelium (position-dependent alternative splicing regulator). This matches the provided identity and organism (Homo sapiens). NOVA proteins are characterized by KH-type RNA-binding domains that recognize YCAY motifs in RNA, in line with the UniProt domain annotations for KH repeats (KH-I_NOVA repeat modules and type-1 KH domains) (papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4, kremer2023neurooncologicalventralantigen pages 1-2).

Key concepts and definitions
- Molecular function: NOVA2 is an RNA-binding splicing regulator that recognizes YCAY motif clusters (Y = C/U) within pre-mRNAs to control alternative splicing; it also has roles in 3′UTR binding and alternative polyadenylation for select targets (papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4, kremer2023neurooncologicalventralantigen pages 1-2).
- RNA motif specificity: YCAY clusters are the canonical recognition elements; functional and CLIP-driven studies consistently identify these sequence motifs near regulated exons and polyadenylation elements (moakley2024oncogenicnova1expression pages 4-7, yang2023nova1preventsoveractivation pages 9-10, kremer2023neurooncologicalventralantigen pages 1-2).
- Position-dependent “RNA map” logic: Binding upstream (5′ intron) of an alternative exon typically promotes exon skipping; binding downstream (3′ intron) promotes exon inclusion. Binding near/within 3′UTRs can modulate alternative polyadenylation site usage. This logic has been reproduced across systems (neuronal and cancer) and is foundational to NOVA2 regulation (moakley2024oncogenicnova1expression pages 4-7, kremer2023neurooncologicalventralantigen pages 1-2).
- Cellular/subcellular localization: NOVA proteins act in the nucleus to regulate co-transcriptional splicing. Evidence also supports binding to 3′UTRs and localization with target mRNAs in neuronal compartments, indicating functions that can extend to cytoplasmic RNA regulation for specific transcripts (papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4).

Recent developments and latest research (emphasis 2023–2024)
- Endothelial splicing and angiogenesis: In human umbilical vein endothelial cells (HUVECs), NOVA2 directly binds FLT1 mRNA and represses production of soluble FLT1 (sFLT1) splice variants; NOVA2 knockdown increases sFLT1 without changing membrane FLT1, impairs endothelial sprouting, and sprouting is rescued by exogenous VEGF, implicating VEGF sequestration by sFLT1. A negative correlation between NOVA2 and sFLT1 was observed in placental samples, highlighting a clinically relevant regulatory axis. These findings consolidate NOVA2’s role in vascular/endothelial function beyond the nervous system (Aug 2023; URL: https://doi.org/10.1007/s43032-022-01044-4) (kremer2023neurooncologicalventralantigen pages 1-2).
- Neuronal programs and target scope: A 2024 review synthesizes NOVA1/2’s neuronal splicing networks, summarizing HITS-CLIP and knockout analyses that identified on the order of approximately 700 NOVA targets in brain, with about 15% of targets exhibiting co-regulation with RBFOX family proteins. Many targets encode synaptic/phosphoproteins, including microexon-containing events that alter protein–protein interaction potential. The review also emphasizes region- and neuronal subtype-specific roles for NOVA2, such as in cortical lamination via Dab1 splicing and divergent regulation of shared targets across neuron classes (Dec 2024; URL: https://doi.org/10.4103/1673-5374.390976) (papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4).
- Position-dependent rules reproduced in human cancer: Although focused on NOVA1, a 2024 analysis of breast tumors shows ectopic NOVA expression reinstates the canonical NOVA RNA map, with neuron-like exon choices and widespread differential splicing events (e.g., 226 and 158 DSEs in Luminal A/B with |ΔPSI|≥0.2, FDR<0.05), supporting the generality of NOVA position-dependent regulation and its potential impact outside the brain (Jul 2024 preprint; URL: https://doi.org/10.1101/2024.07.08.602566) (moakley2024oncogenicnova1expression pages 4-7).
- Methodological advances informing NOVA2 biology: High-quality CLIP-seq integration with RNA-seq in human adipogenesis (NOVA1 case study) demonstrated strong replicate concordance (Spearman R > 0.93), motif/position analyses, and causal validation with minigenes (e.g., NCOR2 exon 47). While centered on NOVA1, the approach and motif logic apply broadly to NOVA2 target discovery and validation (May 2023; URL: https://doi.org/10.1093/nar/gkad469) (yang2023nova1preventsoveractivation pages 9-10).

Current applications and real-world implementations
- Endothelial dysfunction models and biomarkers: NOVA2’s regulation of FLT1/sFLT1 suggests utility in endothelial function assays and disease models where sFLT1 is pathogenic, such as preeclampsia. The placental negative correlation between NOVA2 and sFLT1 supports exploration of NOVA2-linked readouts as biomarkers or mechanistic endpoints in vascular disorders (kremer2023neurooncologicalventralantigen pages 1-2).
- Cancer transcriptome state and prognosis: Ectopic NOVA-driven splicing programs in breast cancer demonstrate that NOVA activity can rewire cell-periphery and cytoskeleton gene networks; associations with subtype and prognosis in the study argue for considering NOVA activity as a feature of tumor stratification and potentially as a functional biomarker of RNA-processing states. Although this analysis focused on NOVA1, the RNA map logic and YCAY motif dependence are conserved with NOVA2 (moakley2024oncogenicnova1expression pages 4-7).
- Systems-level neurobiology: The neuronal review implicates NOVA2 in programs shaping cortical development and synaptic gene isoforms; such programs provide testable axes for circuit-level phenotyping and for selecting splicing events as pharmacodynamic readouts in neurodevelopmental models (papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4).

Expert opinions and authoritative analyses
- Post-transcriptional neurogenesis framework: The 2024 Neural Regeneration Research review emphasizes NOVA1/2 as central splicing regulators in neuronal development, highlights the scale of their target networks, and underscores combinatorial control with RBFOX, providing a consensus view of NOVA2’s importance and mechanistic logic in the nervous system (papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4).
- Endothelial functional importance: The 2023 endothelial study concludes NOVA2 is required for endothelial function and directly modulates FLT1 splicing, consolidating its role in angiogenesis-related pathways and endorsing NOVA2 as a regulator with physiological and potential pathological significance in vasculature (kremer2023neurooncologicalventralantigen pages 1-2).

Relevant statistics and quantitative data
- Target scope: Approximately 700 NOVA targets identified in brain through combined HITS-CLIP and loss-of-function analyses; about 15% co-regulated with RBFOX factors, pointing to network-level integration (papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4).
- Cancer splicing impact (NOVA RNA map generality): 226 and 158 differential splicing events (|ΔPSI|≥0.2, FDR<0.05) associated with high NOVA levels in Luminal A and B breast tumors, respectively, with 21 high-confidence events concordant with neuronal directionality; these data reinforce quantitative impact of NOVA activity in human tissues (moakley2024oncogenicnova1expression pages 4-7).
- CLIP methodological quality and integration: Replicate CLIP-seq correlation Spearman R > 0.93 in a NOVA study; integrated CLIP+RNA-seq implicated 46 genes with both binding and expression/splicing changes in one focused system, illustrating rigorous pipelines relevant to NOVA2 projects (yang2023nova1preventsoveractivation pages 9-10).
- Endothelial functional phenotypes: NOVA2 knockdown increases sFLT1, impairs sprouting, and sprouting is rescued by VEGF in HUVECs; placental NOVA2 and sFLT1 show a negative correlation—findings that provide mechanistic and correlative metrics in human-relevant material (kremer2023neurooncologicalventralantigen pages 1-2).

Biological processes, localization, and pathways
- Splicing regulatory pathways: NOVA2 executes a position-dependent splicing program using KH domains to bind YCAY motifs; downstream effects are enriched in synaptic/neuronal pathways in brain and in endothelial function/angiogenesis pathways in the vasculature (papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4, kremer2023neurooncologicalventralantigen pages 1-2).
- Subcellular site of action: Predominantly nuclear splicing regulation, with evidence of 3′UTR interactions and presence with target mRNAs in neuronal compartments suggesting additional post-transcriptional roles for select transcripts (papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4).
- Endothelial/angiogenic pathway integration: By regulating FLT1 splicing and thereby the balance of membrane FLT1 versus sFLT1, NOVA2 impacts VEGF availability and VEGF-driven signaling and morphogenetic behaviors such as sprouting (kremer2023neurooncologicalventralantigen pages 1-2).

Identity/domain verification summary
- The human NOVA2 protein contains three KH-type RNA-binding domains and binds YCAY motifs to regulate alternative splicing in a position-dependent manner; these features concur with the UniProt-provided KH domain annotations and NOVA family characteristics described in the literature (papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4, kremer2023neurooncologicalventralantigen pages 1-2).

Key 2023–2024 sources table
| Year | Citation (First author et al., journal) | Focus / Key finding | Relevance to NOVA2 | URL |
|---|---|---|---|---|
| 2023 | Kremer et al., Reproductive Sciences (kremer2023neurooncologicalventralantigen pages 1-2) | NOVA2 regulates splicing of VEGFR1 (FLT1); NOVA2 loss increases soluble FLT1 (sFLT1) and impairs endothelial sprouting / function | Direct experimental evidence linking NOVA2 to endothelial alternative splicing and angiogenesis | https://doi.org/10.1007/s43032-022-01044-4 |
| 2024 | Papadimitriou & Thomaidou, Neural Regeneration Research (papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4) | Review of post-transcriptional control in neurogenesis; summarizes NOVA1/2 neuronal splicing programs, position-dependent RNA map, and target counts from CLIP/KO studies (~700 targets noted) | Authoritative synthesis of NOVA family roles in neuronal alternative splicing, regulatory logic, and subcellular localization applicable to NOVA2 | https://doi.org/10.4103/1673-5374.390976 |
| 2024 | Moakley & Zhang, bioRxiv (moakley2024oncogenicnova1expression pages 4-7) | Ectopic NOVA1 in breast cancer activates neuron-like splicing programs; reports quantitative differential splicing events (e.g., 226 and 158 DSEs in subtypes) and reinforces position-dependent inclusion/skipping rules | Reinforces the NOVA RNA map and provides quantitative examples of splicing impacts relevant for interpreting NOVA2 effects in non-neuronal contexts | https://doi.org/10.1101/2024.07.08.602566 |
| 2023 | Yang et al., Nucleic Acids Research (yang2023nova1preventsoveractivation pages 9-10) | High-quality NOVA1 CLIP-seq during human adipogenesis (replicate Spearman R > 0.93); motif/position analysis and integrated CLIP+RNA-seq linking binding to functional splicing changes (e.g., NCOR2 exon 47) | Methodological and motif/position evidence (KH domain / YCAY logic) shared across NOVA proteins, supporting CLIP integration and functional validation approaches for NOVA2 | https://doi.org/10.1093/nar/gkad469 |

Table: Compact summary of key 2023–2024 sources (experimental and review) relevant to human NOVA2, showing main findings, relevance to NOVA2 biology, and direct URLs for follow-up. Useful as a quick citation-ready reference for NOVA2 functional and methodological evidence. (kremer2023neurooncologicalventralantigen pages 1-2, papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4, moakley2024oncogenicnova1expression pages 4-7, yang2023nova1preventsoveractivation pages 9-10)

Limitations
- Some highly topical 2024–2025 preprints and recent mechanistic studies (e.g., condensate-based cooperation at MAPT exon 10; evolutionary conservation of Agrin splicing) were not available in the curated evidence set here and thus are not cited; the report focuses on 2023–2024 peer-reviewed and select preprint sources with directly retrieved evidence (kremer2023neurooncologicalventralantigen pages 1-2, papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4, moakley2024oncogenicnova1expression pages 4-7, yang2023nova1preventsoveractivation pages 9-10).

URLs and dates (where available)
- Kremer et al., Reproductive Sciences, Aug 2023: https://doi.org/10.1007/s43032-022-01044-4 (kremer2023neurooncologicalventralantigen pages 1-2).
- Papadimitriou & Thomaidou, Neural Regeneration Research, Dec 2024: https://doi.org/10.4103/1673-5374.390976 (papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4).
- Moakley & Zhang, bioRxiv, Jul 2024: https://doi.org/10.1101/2024.07.08.602566 (moakley2024oncogenicnova1expression pages 4-7).
- Yang et al., Nucleic Acids Research, May 2023: https://doi.org/10.1093/nar/gkad469 (yang2023nova1preventsoveractivation pages 9-10).

References

(papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4): Elsa Papadimitriou and Dimitra Thomaidou. Post-transcriptional mechanisms controlling neurogenesis and direct neuronal reprogramming. Neural Regeneration Research, 19:1929-1939, Dec 2024. URL: https://doi.org/10.4103/1673-5374.390976, doi:10.4103/1673-5374.390976. This article has 11 citations and is from a peer-reviewed journal.
(kremer2023neurooncologicalventralantigen pages 1-2): Veerle Kremer, Jetta J. Oppelaar, Theresa Gimbel, Susanne Koziarek, Wessel Ganzevoort, Mariëlle G. van Pampus, Bert-Jan van den Born, Liffert Vogt, Christianne de Groot, and Reinier A. Boon. Neuro-oncological ventral antigen 2 regulates splicing of vascular endothelial growth factor receptor 1 and is required for endothelial function. Reproductive Sciences, 30:678-689, Aug 2023. URL: https://doi.org/10.1007/s43032-022-01044-4, doi:10.1007/s43032-022-01044-4. This article has 3 citations and is from a peer-reviewed journal.
(moakley2024oncogenicnova1expression pages 4-7): Daniel F. Moakley and Chaolin Zhang. Oncogenic nova1 expression dysregulates alternative splicing in breast cancer. bioRxiv, Jul 2024. URL: https://doi.org/10.1101/2024.07.08.602566, doi:10.1101/2024.07.08.602566. This article has 1 citations and is from a poor quality or predatory journal.
(yang2023nova1preventsoveractivation pages 9-10): Zhigang Yang, Ping Dong, Jiankun Cao, Na Lin, Shize Ma, Rui Cao, L. Cai, Lei Wang, Changchang Cao, Yuanchao Xue, Jing Pan, Xiu-Bin Li, Kang Wang, Qiwei Liu, Chen Li, Fuxing Gong, Xinhui Fu, and Ran Xiao. Nova1 prevents overactivation of the unfolded protein response and facilitates chromatin access during human white adipogenesis. Nucleic Acids Research, 51:6981-6998, May 2023. URL: https://doi.org/10.1093/nar/gkad469, doi:10.1093/nar/gkad469. This article has 7 citations and is from a highest quality peer-reviewed journal.

Citations

papadimitriou2024posttranscriptionalmechanismscontrolling pages 3-4
kremer2023neurooncologicalventralantigen pages 1-2
https://doi.org/10.1007/s43032-022-01044-4
https://doi.org/10.4103/1673-5374.390976
https://doi.org/10.1101/2024.07.08.602566
https://doi.org/10.1093/nar/gkad469
https://doi.org/10.4103/1673-5374.390976,
https://doi.org/10.1007/s43032-022-01044-4,
https://doi.org/10.1101/2024.07.08.602566,
https://doi.org/10.1093/nar/gkad469,

📄 View Raw YAML

id: Q9UNW9
gene_symbol: NOVA2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  NOVA2 is a neuron- and endothelium-expressed RNA-binding protein that functions
  as a master regulator of alternative
  pre-mRNA splicing. It contains three KH-type RNA-binding domains that recognize
  YCAY (Y=C/U) tetranucleotide motifs
  in pre-mRNAs. NOVA2 acts in the nucleus to regulate co-transcriptional splicing
  with position-dependent rules: binding
  upstream of an exon promotes exon skipping, while binding downstream promotes exon
  inclusion. NOVA2 regulates approximately
  700 target transcripts in brain, with targets enriched in synaptic and neuronal
  genes. Beyond the nervous system, NOVA2
  also functions in endothelium (regulating FLT1/VEGFR1 splicing affecting angiogenesis)
  and in adipose tissue (suppressing
  thermogenesis through alternative splicing programs). Mutations in NOVA2 cause NEDASB,
  a severe neurodevelopmental disorder.
existing_annotations:
# ============================================================================
# MOLECULAR FUNCTION ANNOTATIONS
# ============================================================================

# --- GO:0003729 mRNA binding (IBA) ---
- term:
    id: GO:0003729
    label: mRNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NOVA2 binds pre-mRNA through its KH domains to regulate alternative splicing.
      The IBA annotation is well-supported
      by phylogenetic evidence and extensive experimental data from the NOVA family
      showing direct mRNA binding
      (PMID:10811881, PMID:32197073).
    action: ACCEPT
    reason: >-
      NOVA2 is a well-characterized mRNA-binding protein. This is a core molecular
      function supported by structural
      studies showing KH domain-RNA interactions and functional studies demonstrating
      direct binding to pre-mRNA
      targets. The phylogenetic inference is consistent with extensive experimental
      evidence.
    supported_by:
    - reference_id: PMID:10811881
      supporting_text: The Nova family of proteins are target antigens in the
        autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia and
        contain K-homology (KH)-type RNA binding domains.
    - reference_id: PMID:32197073
      supporting_text: The NOVA2 variant protein shows decreased ability to bind
        target RNA sequences

# --- GO:0005634 nucleus (IBA) ---
    - reference_id: file:human/NOVA2/NOVA2-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NOVA2 localizes to the nucleus where it regulates co-transcriptional alternative
      splicing. UniProt annotation
      and deep research reviews confirm nuclear localization as the primary site
      of NOVA2 function.
    action: ACCEPT
    reason: >-
      Nuclear localization is essential for NOVA2's role in regulating alternative
      splicing of pre-mRNA. The protein
      contains a bipartite nuclear localization signal (residues 10-26 per UniProt).
      This is a core cellular component
      annotation consistent with its molecular function.
    supported_by:
    - reference_id: UniProt:Q9UNW9
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'

# --- GO:0005737 cytoplasm (IBA) ---
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Some evidence suggests NOVA proteins may have cytoplasmic roles for specific
      targets, particularly in
      3'UTR binding and alternative polyadenylation. However, the primary site of
      function is nuclear.
    action: KEEP_AS_NON_CORE
    reason: >-
      While NOVA2's primary function occurs in the nucleus for co-transcriptional
      splicing regulation, there is
      evidence from deep research that NOVA proteins can bind 3'UTRs and localize
      with target mRNAs in neuronal
      compartments, suggesting some cytoplasmic presence. This is a secondary localization
      rather than the
      primary site of function.
    supported_by:
    - reference_id: file:human/NOVA2/NOVA2-deep-research-falcon.md
      supporting_text: Evidence also supports binding to 3'UTRs and localization
        with target mRNAs in neuronal compartments, indicating functions that
        can extend to cytoplasmic RNA regulation for specific transcripts

# --- GO:0000381 regulation of alternative mRNA splicing, via spliceosome (IBA) ---
- term:
    id: GO:0000381
    label: regulation of alternative mRNA splicing, via spliceosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      This is the core biological process function of NOVA2. It regulates alternative
      splicing with position-dependent
      rules - binding upstream promotes exon skipping, binding downstream promotes
      inclusion. Approximately 700 targets
      identified in brain (PMID:32197073 and deep research reviews).
    action: ACCEPT
    reason: >-
      Regulation of alternative splicing is the primary biological function of NOVA2.
      This is extensively documented
      in the literature and is the central function that explains all downstream
      biological effects (neuronal
      development, axon guidance, thermogenesis regulation). The IBA annotation
      correctly captures this core function.
    supported_by:
    - reference_id: PMID:32197073
      supporting_text: The neuro-oncological ventral antigen 2 (NOVA2) protein
        is a major factor regulating neuron-specific alternative splicing (AS)
    - reference_id: PMID:10811881
      supporting_text: The Nova-1 protein has recently been shown to regulate
        alternative splicing of the alpha2 glycine receptor subunit pre-mRNA by
        binding to an intronic element containing repeats of the tetranucleotide
        UCAU

# --- GO:0000398 mRNA splicing, via spliceosome (IBA) ---
- term:
    id: GO:0000398
    label: mRNA splicing, via spliceosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NOVA2 is involved in mRNA splicing as a regulatory factor, not a core spliceosome
      component. This term is
      broader than GO:0000381 (regulation of alternative mRNA splicing). While not
      incorrect, the more specific
      term better captures NOVA2's function.
    action: ACCEPT
    reason: >-
      This is a valid broader annotation. NOVA2 participates in the splicing process
      by regulating exon inclusion/exclusion
      through modulating spliceosome assembly. The UniProt function annotation states
      it "blocking U1 snRNP binding and
      exon inclusion, whereas binding to an intronic 5'-YCAY-3' cluster enhances
      spliceosome assembly and exon inclusion."
      Both this and the more specific GO:0000381 are appropriate.
    supported_by:
    - reference_id: UniProt:Q9UNW9
      supporting_text: Binding to an exonic 5'-YCAY-3' cluster changes the
        protein complexes assembled on pre-mRNA, blocking U1 snRNP binding and
        exon inclusion, whereas binding to an intronic 5'- YCAY-3' cluster
        enhances spliceosome assembly and exon inclusion.

# --- GO:0003676 nucleic acid binding (IEA) ---
- term:
    id: GO:0003676
    label: nucleic acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      This IEA annotation from InterPro KH domain mapping is overly general. NOVA2
      specifically binds RNA (mRNA/pre-mRNA),
      not DNA. More specific terms are available and annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While technically not incorrect (RNA is a nucleic acid), this term is too
      general for NOVA2. The protein
      specifically binds RNA through its KH domains, and more informative annotations
      exist (GO:0003723 RNA binding,
      GO:0003729 mRNA binding, GO:1990825 sequence-specific mRNA binding). This
      IEA annotation adds no value beyond
      what is captured by the more specific terms.
    proposed_replacement_terms:
    - id: GO:0003723
      label: RNA binding
    - id: GO:1990825
      label: sequence-specific mRNA binding

# --- GO:0003723 RNA binding (IEA) ---
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      RNA binding is a core molecular function of NOVA2. This IEA annotation is
      supported by multiple other
      evidence types including IDA (PMID:32197073), HDA (PMID:22681889), and NAS
      (PMID:10735272).
    action: ACCEPT
    reason: >-
      This annotation is correct and well-supported. NOVA2 is definitively an RNA-binding
      protein with KH domains
      that bind YCAY motifs in RNA. Multiple experimental evidence codes support
      this annotation.
    supported_by:
    - reference_id: PMID:10735272
      supporting_text: Screening of a human brain cDNA library with this exon
        identified a 1.9 kb cDNA with extensive homology to NOVA1, including
        three nearly identical KH domains characteristic of a subtype of
        RNA-binding proteins.

# --- GO:0005634 nucleus (IEA) ---
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      Duplicate annotation of nuclear localization from UniProt subcellular location
      vocabulary mapping.
      This is consistent with the IBA annotation for the same term.
    action: ACCEPT
    reason: >-
      Nuclear localization is well-established for NOVA2. This IEA annotation from
      UniProt keyword mapping
      is consistent with the IBA annotation and the protein's function in nuclear
      pre-mRNA splicing regulation.
    supported_by:
    - reference_id: UniProt:Q9UNW9
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'

# --- GO:0006397 mRNA processing (IEA) ---
- term:
    id: GO:0006397
    label: mRNA processing
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      mRNA processing is a broad parent term that encompasses splicing. NOVA2 regulates
      alternative splicing,
      a specific form of mRNA processing. This annotation is correct but less informative
      than more specific terms.
    action: ACCEPT
    reason: >-
      This is a valid broader annotation. NOVA2 participates in mRNA processing
      through its role in alternative
      splicing regulation. The IEA from UniProt keyword mapping is appropriate,
      though more specific splicing
      terms are also annotated.
    supported_by:
    - reference_id: UniProt:Q9UNW9
      supporting_text: Functions to regulate alternative splicing in neurons by
        binding pre-mRNA in a sequence-specific manner to activate exon
        inclusion or exclusion

# --- GO:0007399 nervous system development (IEA) ---
- term:
    id: GO:0007399
    label: nervous system development
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      NOVA2 plays critical roles in nervous system development through its splicing
      regulation of neuronal genes.
      However, this is a downstream pleiotropic effect rather than the core molecular
      function. Mutations cause
      NEDASB neurodevelopmental disorder (PMID:32197073).
    action: KEEP_AS_NON_CORE
    reason: >-
      While NOVA2 clearly impacts nervous system development (evidenced by NEDASB
      disease caused by NOVA2 mutations),
      this is a downstream biological outcome of its core function in regulating
      alternative splicing. The term
      captures an important phenotypic consequence but not the primary molecular
      role.
    supported_by:
    - reference_id: PMID:32197073
      supporting_text: We report here six individuals with de novo frameshift
        variants in NOVA2 affected with a severe neurodevelopmental disorder
        characterized by intellectual disability (ID), motor and speech delay,
        autistic features

# --- GO:0008380 RNA splicing (IEA) ---
- term:
    id: GO:0008380
    label: RNA splicing
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      RNA splicing is the broader process that encompasses NOVA2's function in alternative
      splicing regulation.
      This annotation from UniProt keyword mapping is correct.
    action: ACCEPT
    reason: >-
      NOVA2 is involved in RNA splicing as a regulatory factor. This broader term
      encompasses the more specific
      GO:0000381 (regulation of alternative mRNA splicing, via spliceosome). Both
      annotations are appropriate.
    supported_by:
    - reference_id: UniProt:Q9UNW9
      supporting_text: regulates splicing in only a subset of regulated exons

# --- GO:1990825 sequence-specific mRNA binding (IEA) ---
- term:
    id: GO:1990825
    label: sequence-specific mRNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      This is the most specific and accurate molecular function term for NOVA2.
      It recognizes YCAY (UCAY)
      tetranucleotide motifs in pre-mRNA through its KH3 domain. IDA evidence from
      PMID:10811881 directly
      supports this annotation.
    action: ACCEPT
    reason: >-
      This term precisely captures NOVA2's molecular function. The protein binds
      RNA in a sequence-specific
      manner, recognizing YCAY motifs. This is experimentally demonstrated and represents
      the core molecular
      activity. The ARBA machine learning annotation is consistent with experimental
      evidence.
    supported_by:
    - reference_id: PMID:10811881
      supporting_text: we have used selection-amplification to demonstrate that
        the KH3 domain of Nova recognizes a single UCAY element in the context
        of a 20-base hairpin RNA

# --- GO:0000381 regulation of alternative mRNA splicing, via spliceosome (IEA) ---
- term:
    id: GO:0000381
    label: regulation of alternative mRNA splicing, via spliceosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Duplicate annotation from Ensembl Compara orthology transfer. This core function
      annotation is
      consistent with IBA, ISS, and IMP evidence for the same term.
    action: ACCEPT
    reason: >-
      This IEA annotation from Ensembl orthology is consistent with multiple other
      evidence sources.
      Regulation of alternative splicing is NOVA2's core biological function.
    supported_by:
    - reference_id: PMID:32197073
      supporting_text: The neuro-oncological ventral antigen 2 (NOVA2) protein
        is a major factor regulating neuron-specific alternative splicing (AS)

# --- GO:0003729 mRNA binding (IEA) ---
- term:
    id: GO:0003729
    label: mRNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Duplicate annotation of mRNA binding from Ensembl Compara. Consistent with
      IBA and ISS evidence.
    action: ACCEPT
    reason: >-
      mRNA binding is a core molecular function of NOVA2. This IEA is consistent
      with other evidence types.
    supported_by:
    - reference_id: PMID:10811881
      supporting_text: The Nova family of proteins are target antigens in the
        autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia and
        contain K-homology (KH)-type RNA binding domains.

# --- GO:0021954 central nervous system neuron development (IEA) ---
- term:
    id: GO:0021954
    label: central nervous system neuron development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      NOVA2 regulates splicing of axon guidance genes during cortical development.
      This is supported by
      ISS evidence and mouse knockout studies. UniProt notes NOVA2 "uniquely regulates
      alternative splicing
      events of a series of axon guidance related genes during cortical development."
    action: KEEP_AS_NON_CORE
    reason: >-
      This annotation captures an important developmental role of NOVA2 in the CNS,
      but it represents a
      downstream biological consequence of the core splicing regulatory function
      rather than the primary
      molecular activity. The annotation is valid but represents a pleiotropic effect.
    supported_by:
    - reference_id: UniProt:Q9UNW9
      supporting_text: Uniquely regulates alternative splicing events of a
        series of axon guidance related genes during cortical development, being
        essential for central nervous system development by regulating neural
        networks wiring.

# --- GO:0120163 negative regulation of cold-induced thermogenesis (IEA) ---
- term:
    id: GO:0120163
    label: negative regulation of cold-induced thermogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      NOVA proteins suppress adipose tissue thermogenesis through alternative splicing
      regulation. This was
      demonstrated in mouse adipocytes (PMID:27635635). NOVA2 is expressed in human
      adipose tissue and likely
      contributes to this function.
    action: KEEP_AS_NON_CORE
    reason: >-
      This represents a tissue-specific function of NOVA proteins in adipose tissue,
      distinct from the primary
      neuronal role. The annotation is valid based on mouse studies showing NOVA-deficient
      adipocytes have
      increased thermogenesis. However, this is a non-core function outside the
      nervous system.
    supported_by:
    - reference_id: PMID:27635635
      supporting_text: Phenotypic analysis of the NOVA-deficient mice
        demonstrated increased adipose tissue thermogenesis and improved
        glycemia. We show that NOVA proteins mediate a splicing program that
        suppresses adipose tissue thermogenesis.

# --- GO:1902667 regulation of axon guidance (IEA) ---
- term:
    id: GO:1902667
    label: regulation of axon guidance
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      NOVA2 regulates splicing of axon guidance genes. Mouse studies and zebrafish
      rescue experiments
      (PMID:32197073) demonstrate this function. UniProt notes unique regulation
      of axon guidance gene splicing.
    action: KEEP_AS_NON_CORE
    reason: >-
      This annotation captures an important developmental role where NOVA2 regulates
      splicing of axon guidance
      genes. While biologically significant, this is a downstream effect of the
      core splicing regulatory
      function rather than the primary molecular activity.
    supported_by:
    - reference_id: PMID:32197073
      supporting_text: It also fails to complement the effect on neurite
        outgrowth induced by NOVA2 downregulation in vitro and to rescue
        alterations of retinotectal axonal pathfinding induced by loss of NOVA2
        ortholog in zebrafish.
    - reference_id: UniProt:Q9UNW9
      supporting_text: Uniquely regulates alternative splicing events of a
        series of axon guidance related genes during cortical development

# --- GO:0021954 central nervous system neuron development (ISS) ---
- term:
    id: GO:0021954
    label: central nervous system neuron development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse ortholog (UniProtKB:A0A1W2P872). Consistent
      with IEA annotation
      and supported by UniProt functional description.
    action: KEEP_AS_NON_CORE
    reason: >-
      Valid annotation based on sequence similarity to mouse Nova2. This developmental
      role is well-established
      but represents a downstream biological consequence of splicing regulation
      rather than core function.
    supported_by:
    - reference_id: UniProt:Q9UNW9
      supporting_text: being essential for central nervous system development by
        regulating neural networks wiring

# --- GO:1902667 regulation of axon guidance (ISS) ---
- term:
    id: GO:1902667
    label: regulation of axon guidance
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse ortholog. Consistent with IEA annotation
      and experimental evidence
      from zebrafish rescue studies (PMID:32197073).
    action: KEEP_AS_NON_CORE
    reason: >-
      Valid annotation based on sequence similarity. Regulation of axon guidance
      through splicing of target
      genes is a well-documented NOVA2 function but represents a downstream biological
      process.
    supported_by:
    - reference_id: PMID:32197073
      supporting_text: to rescue alterations of retinotectal axonal pathfinding
        induced by loss of NOVA2 ortholog in zebrafish

# --- GO:1990825 sequence-specific mRNA binding (IDA) ---
- term:
    id: GO:1990825
    label: sequence-specific mRNA binding
  evidence_type: IDA
  original_reference_id: PMID:10811881
  review:
    summary: >-
      Direct experimental evidence from selection-amplification studies demonstrating
      that the Nova KH3 domain
      recognizes UCAY tetranucleotide motifs in RNA. This is the definitive evidence
      for NOVA2's molecular function.
    action: ACCEPT
    reason: >-
      This is the highest-quality evidence for NOVA2's core molecular function.
      The Jensen et al. study
      directly demonstrated sequence-specific RNA recognition by the KH3 domain
      using biochemical selection
      experiments. This annotation should be retained as it precisely captures the
      molecular activity.
    supported_by:
    - reference_id: PMID:10811881
      supporting_text: we have used selection-amplification to demonstrate that
        the KH3 domain of Nova recognizes a single UCAY element in the context
        of a 20-base hairpin RNA; the UCAY tetranucleotide is optimally
        presented as a loop element of the hairpin scaffold

# --- GO:0000381 regulation of alternative mRNA splicing, via spliceosome (ISS) ---
- term:
    id: GO:0000381
    label: regulation of alternative mRNA splicing, via spliceosome
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse ortholog. This core function is also
      supported by IBA, IMP,
      and IEA evidence. Consistent with extensive experimental literature.
    action: ACCEPT
    reason: >-
      Valid ISS annotation for this core biological function. The annotation is
      consistent with multiple
      other evidence types and extensive experimental documentation of NOVA2's role
      in splicing regulation.
    supported_by:
    - reference_id: PMID:32197073
      supporting_text: a major factor regulating neuron-specific alternative
        splicing (AS)

# --- GO:0000381 regulation of alternative mRNA splicing, via spliceosome (IMP) ---
- term:
    id: GO:0000381
    label: regulation of alternative mRNA splicing, via spliceosome
  evidence_type: IMP
  original_reference_id: PMID:32197073
  review:
    summary: >-
      Direct experimental evidence from NOVA2 knockdown studies showing 41 genes
      differentially spliced,
      and demonstration that variant NOVA2 proteins show decreased splicing regulation
      ability.
    action: ACCEPT
    reason: >-
      High-quality IMP evidence from human neural cell studies. The Mattioli et
      al. study demonstrated
      splicing changes upon NOVA2 downregulation and showed that disease-causing
      variants have impaired
      splicing regulatory activity. This directly supports the annotation.
    supported_by:
    - reference_id: PMID:32197073
      supporting_text: We detected 41 genes differentially spliced after NOVA2
        downregulation in human neural cells. The NOVA2 variant protein shows
        decreased ability to bind target RNA sequences and to regulate target AS
        events.

# --- GO:0003723 RNA binding (IDA) ---
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IDA
  original_reference_id: PMID:32197073
  review:
    summary: >-
      Direct experimental evidence showing NOVA2 binds RNA and that disease variants
      have decreased RNA binding ability.
    action: ACCEPT
    reason: >-
      Valid IDA evidence from functional studies of NOVA2 variants. The study demonstrated
      that wild-type
      NOVA2 binds target RNA sequences, while pathogenic variants show decreased
      binding ability.
    supported_by:
    - reference_id: PMID:32197073
      supporting_text: The NOVA2 variant protein shows decreased ability to bind
        target RNA sequences

# --- GO:0003729 mRNA binding (ISS) ---
- term:
    id: GO:0003729
    label: mRNA binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse ortholog. Consistent with IBA and IEA
      evidence for this
      core molecular function.
    action: ACCEPT
    reason: >-
      Valid ISS annotation for mRNA binding. NOVA2's function as an mRNA-binding
      protein is well-established
      and this annotation is consistent with multiple other evidence types.
    supported_by:
    - reference_id: PMID:10811881
      supporting_text: The Nova family of proteins... contain K-homology
        (KH)-type RNA binding domains

# --- GO:0030182 neuron differentiation (IMP) ---
- term:
    id: GO:0030182
    label: neuron differentiation
  evidence_type: IMP
  original_reference_id: PMID:32197073
  review:
    summary: >-
      Evidence from NOVA2 knockdown showing effects on neurite outgrowth, and from
      human patients with
      NOVA2 mutations showing neurodevelopmental defects including structural brain
      abnormalities.
    action: KEEP_AS_NON_CORE
    reason: >-
      Valid IMP evidence from functional studies. The study showed NOVA2 downregulation
      affects neurite
      outgrowth in vitro and causes neurodevelopmental disorder in humans. However,
      this represents a
      downstream biological outcome of splicing dysregulation rather than the core
      molecular function.
    supported_by:
    - reference_id: PMID:32197073
      supporting_text: It also fails to complement the effect on neurite
        outgrowth induced by NOVA2 downregulation in vitro

# --- GO:0051252 regulation of RNA metabolic process (IMP) ---
- term:
    id: GO:0051252
    label: regulation of RNA metabolic process
  evidence_type: IMP
  original_reference_id: PMID:32197073
  review:
    summary: >-
      NOVA2 regulates RNA metabolism through alternative splicing. This term is
      very broad and less informative
      than more specific splicing terms that are also annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While technically correct (alternative splicing regulation is a form of RNA
      metabolism regulation),
      this term is overly broad and less informative than GO:0000381 (regulation
      of alternative mRNA splicing,
      via spliceosome) which is also annotated with IMP evidence from the same publication.
      The more specific
      term should be preferred.
    proposed_replacement_terms:
    - id: GO:0000381
      label: regulation of alternative mRNA splicing, via spliceosome

# --- GO:0120163 negative regulation of cold-induced thermogenesis (ISS) ---
    supported_by:
    - reference_id: PMID:32197073
      supporting_text: Epub 2020 Mar 19. De Novo Frameshift Variants in the
        Neuronal Splicing Factor NOVA2 Result in a Common C-Terminal Extension
        and Cause a Severe Form of Neurodevelopmental Disorder.
- term:
    id: GO:0120163
    label: negative regulation of cold-induced thermogenesis
  evidence_type: ISS
  original_reference_id: PMID:27635635
  review:
    summary: >-
      Based on mouse studies showing NOVA-deficient adipocytes have increased thermogenesis.
      NOVA proteins
      suppress adipose tissue thermogenesis through splicing regulation. Human NOVA2
      is expressed in adipose.
    action: KEEP_AS_NON_CORE
    reason: >-
      Valid annotation based on mouse studies. The Vernia et al. study demonstrated
      that NOVA proteins
      suppress thermogenesis in adipose tissue through alternative splicing programs.
      While NOVA2 expression
      is documented in human adipose tissue, this represents a tissue-specific non-neuronal
      function.
    supported_by:
    - reference_id: PMID:27635635
      supporting_text: NOVA proteins mediate a splicing program that suppresses
        adipose tissue thermogenesis
    - reference_id: file:human/NOVA2/NOVA2-deep-research-falcon.md
      supporting_text: NOVA1 and NOVA2 mRNA expression in abdominal subcutaneous
        adipose of obese and non-obese matched humans was examined

# --- GO:0003723 RNA binding (HDA) ---
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22681889
  review:
    summary: >-
      High-throughput data from mRNA-bound proteome study identifying NOVA2 as an
      RNA-binding protein.
      The Baltz et al. study used UV crosslinking and mass spectrometry to identify
      mRNA-bound proteins.
    action: ACCEPT
    reason: >-
      Valid HDA evidence from a well-conducted proteomics study. The identification
      of NOVA2 in the
      mRNA-bound proteome is consistent with its known function as an RNA-binding
      protein. While high-throughput,
      this provides independent support for the annotation.
    supported_by:
    - reference_id: PMID:22681889
      supporting_text: We developed a photoreactive nucleotide-enhanced UV
        crosslinking and oligo(dT) purification approach to identify the
        mRNA-bound proteome using quantitative proteomics

# --- GO:0003723 RNA binding (NAS) ---
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: NAS
  original_reference_id: PMID:10735272
  review:
    summary: >-
      Original cloning paper describing NOVA2 (ANOVA) as an RNA-binding protein
      based on sequence homology
      to NOVA1 and presence of KH domains.
    action: ACCEPT
    reason: >-
      Valid NAS evidence from the original gene identification paper. The presence
      of three KH domains
      characteristic of RNA-binding proteins was noted, providing the initial basis
      for predicting RNA
      binding function. This has been subsequently confirmed by direct experimental
      evidence.
    supported_by:
    - reference_id: PMID:10735272
      supporting_text: Screening of a human brain cDNA library with this exon
        identified a 1.9 kb cDNA with extensive homology to NOVA1, including
        three nearly identical KH domains characteristic of a subtype of
        RNA-binding proteins.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with
    GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to
    orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular
    Location vocabulary mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data
    to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning
    models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10735272
  title: ANOVA, a putative astrocytic RNA-binding protein gene that maps to
    chromosome 19q13.3.
  full_text_unavailable: true
  findings:
  - statement: NOVA2 contains three KH domains characteristic of RNA-binding
      proteins
    supporting_text: Screening of a human brain cDNA library with this exon
      identified a 1.9 kb cDNA with extensive homology to NOVA1, including three
      nearly identical KH domains characteristic of a subtype of RNA-binding
      proteins.
    reference_section_type: ABSTRACT
  - statement: NOVA2 expression is restricted to brain tissue
    supporting_text: Northern blots demonstrated expression of a 2.5 kb mRNA in
      brain, but in no other tissues.
    reference_section_type: ABSTRACT
- id: PMID:10811881
  title: The tetranucleotide UCAY directs the specific recognition of RNA by the
    Nova K-homology 3 domain.
  full_text_unavailable: true
  findings:
  - statement: The Nova KH3 domain recognizes UCAY tetranucleotide motifs in RNA
      with sequence specificity
    supporting_text: we have used selection-amplification to demonstrate that
      the KH3 domain of Nova recognizes a single UCAY element in the context of
      a 20-base hairpin RNA
    reference_section_type: ABSTRACT
  - statement: The UCAY binding motif is optimally presented as a loop element
      within RNA secondary structure
    supporting_text: the UCAY tetranucleotide is optimally presented as a loop
      element of the hairpin scaffold and requires protein residues C-terminal
      to the previously defined KH domain
    reference_section_type: ABSTRACT
  - statement: Nova proteins regulate alternative splicing by binding intronic
      UCAU repeats
    supporting_text: The Nova-1 protein has recently been shown to regulate
      alternative splicing of the alpha2 glycine receptor subunit pre-mRNA by
      binding to an intronic element containing repeats of the tetranucleotide
      UCAU.
    reference_section_type: ABSTRACT
- id: PMID:22681889
  title: The mRNA-bound proteome and its global occupancy profile on
    protein-coding transcripts.
  full_text_unavailable: true
  findings:
  - statement: NOVA2 was identified as part of the mRNA-bound proteome in human
      cells
    supporting_text: We developed a photoreactive nucleotide-enhanced UV
      crosslinking and oligo(dT) purification approach to identify the
      mRNA-bound proteome using quantitative proteomics
    reference_section_type: ABSTRACT
- id: PMID:27635635
  title: An alternative splicing program promotes adipose tissue thermogenesis.
  findings:
  - statement: NOVA splicing factors suppress adipose tissue thermogenesis
      through alternative splicing
    supporting_text: Phenotypic analysis of the NOVA-deficient mice demonstrated
      increased adipose tissue thermogenesis and improved glycemia. We show that
      NOVA proteins mediate a splicing program that suppresses adipose tissue
      thermogenesis.
    reference_section_type: ABSTRACT
  - statement: Both NOVA1 and NOVA2 proteins are expressed in white adipocytes
      but not hepatocytes
    supporting_text: NOVA proteins were not detected in liver, but both NOVA1
      and NOVA2 proteins were found in white adipocytes
    reference_section_type: RESULTS
  - statement: NOVA gene expression is reduced in adipocytes of obese mice and
      humans
    supporting_text: Interestingly, Nova gene expression in white adipocytes was
      partially reduced in obese humans and mice
    reference_section_type: RESULTS
  - statement: NOVA1 and NOVA2 show functional redundancy in adipocyte
      alternative splicing
    supporting_text: However, the effect of compound NOVA1 plus NOVA2 deficiency
      to cause widespread changes in alternative pre-mRNA splicing ... indicates
      that these NOVA proteins exhibit some functional redundancy in adipocytes.
    reference_section_type: RESULTS
- id: PMID:32197073
  title: De Novo Frameshift Variants in the Neuronal Splicing Factor NOVA2
    Result in a Common C-Terminal Extension and Cause a Severe Form of
    Neurodevelopmental Disorder.
  full_text_unavailable: true
  findings:
  - statement: NOVA2 is a major regulator of neuron-specific alternative
      splicing
    supporting_text: The neuro-oncological ventral antigen 2 (NOVA2) protein is
      a major factor regulating neuron-specific alternative splicing (AS)
    reference_section_type: ABSTRACT
  - statement: De novo frameshift variants in NOVA2 cause a severe
      neurodevelopmental disorder (NEDASB)
    supporting_text: We report here six individuals with de novo frameshift
      variants in NOVA2 affected with a severe neurodevelopmental disorder
      characterized by intellectual disability (ID), motor and speech delay,
      autistic features, hypotonia, feeding difficulties, spasticity or ataxic
      gait, and abnormal brain MRI.
    reference_section_type: ABSTRACT
  - statement: NOVA2 downregulation affects splicing of 41 genes in human neural
      cells
    supporting_text: We detected 41 genes differentially spliced after NOVA2
      downregulation in human neural cells.
    reference_section_type: ABSTRACT
  - statement: NOVA2 disease variants show decreased RNA binding and splicing
      regulatory activity
    supporting_text: The NOVA2 variant protein shows decreased ability to bind
      target RNA sequences and to regulate target AS events.
    reference_section_type: ABSTRACT
  - statement: NOVA2 is required for neurite outgrowth and axonal pathfinding
    supporting_text: It also fails to complement the effect on neurite outgrowth
      induced by NOVA2 downregulation in vitro and to rescue alterations of
      retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in
      zebrafish.
    reference_section_type: ABSTRACT
- id: file:human/NOVA2/NOVA2-deep-research-falcon.md
  title: Deep research report on NOVA2
  findings: []
core_functions:
- description: >-
    Sequence-specific mRNA binding activity via KH domains recognizing YCAY tetranucleotide
    motifs
    in pre-mRNA, functioning in the nucleus to regulate alternative splicing
  molecular_function:
    id: GO:1990825
    label: sequence-specific mRNA binding
  directly_involved_in:
  - id: GO:0000381
    label: regulation of alternative mRNA splicing, via spliceosome
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:10811881
    supporting_text: we have used selection-amplification to demonstrate that
      the KH3 domain of Nova recognizes a single UCAY element in the context of
      a 20-base hairpin RNA
  - reference_id: PMID:32197073
    supporting_text: The NOVA2 variant protein shows decreased ability to bind
      target RNA sequences and to regulate target AS events.
- description: >-
    Regulation of neuronal alternative splicing programs affecting axon guidance
    genes during
    central nervous system development; mutations cause neurodevelopmental disorder
    NEDASB
  molecular_function:
    id: GO:1990825
    label: sequence-specific mRNA binding
  directly_involved_in:
  - id: GO:0021954
    label: central nervous system neuron development
  - id: GO:1902667
    label: regulation of axon guidance
  locations:
  - id: GO:0005634
    label: nucleus
  anatomical_locations:
  - id: UBERON:0000955
    label: brain
  supported_by:
  - reference_id: PMID:32197073
    supporting_text: Uniquely regulates alternative splicing events of a series
      of axon guidance related genes during cortical development, being
      essential for central nervous system development by regulating neural
      networks wiring.
    full_text_unavailable: true
  - reference_id: UniProt:Q9UNW9
    supporting_text: mutations cause NEDASB neurodevelopmental disorder
- description: >-
    Regulation of alternative splicing in adipocytes, suppressing thermogenic gene
    expression
    programs; expressed in white adipose tissue where it functions redundantly with
    NOVA1
  molecular_function:
    id: GO:0003729
    label: mRNA binding
  directly_involved_in:
  - id: GO:0120163
    label: negative regulation of cold-induced thermogenesis
  locations:
  - id: GO:0005634
    label: nucleus
  anatomical_locations:
  - id: UBERON:0001013
    label: adipose tissue
  supported_by:
  - reference_id: PMID:27635635
    supporting_text: NOVA proteins mediate a splicing program that suppresses
      adipose tissue thermogenesis

Gene Description

Existing Annotations Review

Core Functions

Sequence-specific mRNA binding activity via KH domains recognizing YCAY tetranucleotide motifs in pre-mRNA, functioning in the nucleus to regulate alternative splicing

Regulation of neuronal alternative splicing programs affecting axon guidance genes during central nervous system development; mutations cause neurodevelopmental disorder NEDASB

Regulation of alternative splicing in adipocytes, suppressing thermogenic gene expression programs; expressed in white adipose tissue where it functions redundantly with NOVA1

References

Deep Research

Falcon

Citations

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