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.

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

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