DPYSL5

# yaml-language-server: $schema=../../../src/ai_gene_review/schema/gene_review.yaml
id: Q9BPU6
gene_symbol: DPYSL5
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'Dihydropyrimidinase-related protein 5 (DPYSL5; also CRMP5, CRAM, DRP-5, ULIP-6), a brain-enriched
  cytoplasmic member of the collapsin response mediator protein (CRMP) / dihydropyrimidinase-related family.
  Although it is ~57% identical to dihydropyrimidinase and belongs to the metallo-dependent hydrolase
  (amidohydrolase) superfamily, DPYSL5 lacks the conserved metal-cofactor-binding residues required for
  catalysis and has no dihydropyrimidinase / amidohydrolase activity - it is a catalytically dead (pseudoenzyme)
  family member. Its function is as a cytoskeleton-associated regulator of neuronal morphogenesis: it
  negatively regulates dendrite/neurite outgrowth and is most highly expressed in fetal and neonatal brain,
  where it is up-regulated during neuronal differentiation. DPYSL5 forms homotetramers and heterotetramers
  with other CRMP-family proteins (notably DPYSL2/CRMP2) and associates with CRMP3 and protein-tyrosine
  kinases, acting within the semaphorin/collapsin growth-cone signalling system. Loss-of-function and
  dominant missense variants cause a neurodevelopmental disorder featuring agenesis of the corpus callosum
  and cerebellar abnormalities.'
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: 'DPYSL5/CRMP5 is a cytosolic protein (UniProt: Cytoplasm). is_active_in cytosol by phylogenetic
      inference is consistent with the CRMP family and with its role as a cytoskeleton-associated regulator.'
    action: ACCEPT
    reason: Correct localization. CRMPs are soluble cytoplasmic proteins; UniProt records DPYSL5 as cytoplasmic.
    supported_by:
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0004157
    label: dihydropyrimidinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  negated: true
  review:
    summary: 'This is a NOT (negated) annotation: DPYSL5 does NOT enable dihydropyrimidinase activity.
      Although DPYSL5 belongs to the metallo-dependent hydrolase (dihydropyrimidinase/amidohydrolase)
      superfamily and is ~57% identical to dihydropyrimidinase, it lacks the conserved metal-cofactor-binding
      residues required for catalysis (UniProt CAUTION).'
    action: ACCEPT
    reason: The negation is correct and important. DPYSL5 is a catalytically dead family member; the curated
      NOT|enables faithfully encodes the loss of activity flagged by the UniProt CAUTION. Retain as-is.
    supported_by:
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: Lacks most of the conserved residues that are essential for binding the metal cofactor
        and hence for dihydropyrimidinase activity.
- term:
    id: GO:0006208
    label: pyrimidine nucleobase catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  negated: true
  review:
    summary: 'NOT (negated) annotation: DPYSL5 is NOT involved in pyrimidine nucleobase catabolism. This
      is the process counterpart of the absent dihydropyrimidinase activity.'
    action: ACCEPT
    reason: Correct negation, consistent with the loss of catalytic activity (no metal cofactor binding).
      Retain.
    supported_by:
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: Lacks most of the conserved residues that are essential for binding the metal cofactor
        and hence for dihydropyrimidinase activity.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Cytoplasmic localization by automated IEA, consistent with UniProt and with the IBA cytosol
      annotation.
    action: ACCEPT
    reason: Correct, if broad, localization. CRMP5 is a cytoplasmic protein.
    supported_by:
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Positive IEA 'hydrolase activity' propagated from the metallo-dependent hydrolase fold signature
      (InterPro IPR006680, Amidohydrolase-related). DPYSL5 belongs to this superfamily by sequence, but
      the UniProt CAUTION states it lacks the conserved metal-cofactor-binding residues 'essential for
      ... dihydropyrimidinase activity', and metallo-hydrolase catalysis across this superfamily depends
      on that metal centre.
    action: REMOVE
    reason: 'Domain-based electronic over-propagation that should be removed on biological grounds. The
      annotation rests solely on the fold signature; the catalytic prerequisite (metal-cofactor binding)
      is demonstrably absent, the curated GO:0004157 (dihydropyrimidinase) is itself NOT-ed, and there
      is no positive evidence DPYSL5 performs any hydrolysis. Its established function is non-catalytic
      (negative regulation of dendrite outgrowth). NB: this is not a logical contradiction with the NOT
      (GO NOT propagates to child terms, not up to parents) - it is an unsupported, biologically implausible
      over-annotation. A weaker action (MARK_AS_OVER_ANNOTATED) does not fit, since that is for terms
      the gene is genuinely related to but peripheral on; here the activity is absent.'
    supported_by:
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: Lacks most of the conserved residues that are essential for binding the metal cofactor
        and hence for dihydropyrimidinase activity.
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: Belongs to the metallo-dependent hydrolases superfamily.
- term:
    id: GO:0016810
    label: hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Positive IEA 'hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds' propagated
      from the metallo-dependent hydrolase composite fold (InterPro IPR011059). Same basis and same problem
      as the GO:0016787 parent term.
    action: REMOVE
    reason: Domain-based over-propagation contradicted on biological grounds by the loss of metal-cofactor-binding
      residues (UniProt CAUTION). No positive evidence of any C-N hydrolase activity; curated dihydropyrimidinase
      activity is NOT-ed. Remove, consistent with the GO:0016787 removal.
    supported_by:
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: Lacks most of the conserved residues that are essential for binding the metal cofactor
        and hence for dihydropyrimidinase activity.
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: Belongs to the metallo-dependent hydrolases superfamily.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: IPI 'protein binding' annotation; the with/from partner is DPYSL2/CRMP2 (Q16555). DPYSL5
      forms homo- and hetero-oligomers with other CRMP-family members, so this captures a real CRMP5-CRMP2
      interaction.
    action: KEEP_AS_NON_CORE
    reason: The interaction is biologically meaningful (CRMP hetero-oligomerization) but the generic 'protein
      binding' term is uninformative about molecular function (curation guideline). Keep as non-core supporting
      evidence for oligomerization rather than as a core function.
    supported_by: &id001
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: Homotetramer, and heterotetramer with other DPYS-like proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: IPI 'protein binding' annotation; the with/from partner is DPYSL2/CRMP2 (Q16555). DPYSL5
      forms homo- and hetero-oligomers with other CRMP-family members, so this captures a real CRMP5-CRMP2
      interaction.
    action: KEEP_AS_NON_CORE
    reason: The interaction is biologically meaningful (CRMP hetero-oligomerization) but the generic 'protein
      binding' term is uninformative about molecular function (curation guideline). Keep as non-core supporting
      evidence for oligomerization rather than as a core function.
    supported_by: *id001
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29892012
  qualifier: enables
  review:
    summary: IPI 'protein binding' annotation; the with/from partner is DPYSL2/CRMP2 (Q16555). DPYSL5
      forms homo- and hetero-oligomers with other CRMP-family members, so this captures a real CRMP5-CRMP2
      interaction.
    action: KEEP_AS_NON_CORE
    reason: The interaction is biologically meaningful (CRMP hetero-oligomerization) but the generic 'protein
      binding' term is uninformative about molecular function (curation guideline). Keep as non-core supporting
      evidence for oligomerization rather than as a core function.
    supported_by: *id001
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: IPI 'protein binding' annotation; the with/from partner is DPYSL2/CRMP2 (Q16555). DPYSL5
      forms homo- and hetero-oligomers with other CRMP-family members, so this captures a real CRMP5-CRMP2
      interaction.
    action: KEEP_AS_NON_CORE
    reason: The interaction is biologically meaningful (CRMP hetero-oligomerization) but the generic 'protein
      binding' term is uninformative about molecular function (curation guideline). Keep as non-core supporting
      evidence for oligomerization rather than as a core function.
    supported_by: *id001
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic 'protein binding' from a large-scale interactome screen. Uninformative about DPYSL5's
      molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome 'protein binding' carries no specific functional signal; per curation
      guidelines avoid 'protein binding' in favour of informative MF terms. Over-annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Generic 'protein binding' from a large-scale interactome screen. Uninformative about DPYSL5's
      molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome 'protein binding' carries no specific functional signal; per curation
      guidelines avoid 'protein binding' in favour of informative MF terms. Over-annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: IPI 'protein binding' annotation; the with/from partner is DPYSL2/CRMP2 (Q16555). DPYSL5
      forms homo- and hetero-oligomers with other CRMP-family members, so this captures a real CRMP5-CRMP2
      interaction.
    action: KEEP_AS_NON_CORE
    reason: The interaction is biologically meaningful (CRMP hetero-oligomerization) but the generic 'protein
      binding' term is uninformative about molecular function (curation guideline). Keep as non-core supporting
      evidence for oligomerization rather than as a core function.
    supported_by: *id001
- term:
    id: GO:0030182
    label: neuron differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Neuron differentiation (IEA). DPYSL5/CRAM is brain-specific, strongly up-regulated during
      neuronal differentiation and in fetal/neonatal brain.
    action: KEEP_AS_NON_CORE
    reason: Correct but broad developmental process; non-core relative to the specific dendrite-morphogenesis
      role.
    supported_by:
    - reference_id: PMID:10851247
      supporting_text: CRAM expression is up-regulated during neuronal differentiation of embryonal carcinoma
        P19 and PC12 cells
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Dendrite localization (IEA from ortholog transfer), consistent with CRMP5's role in regulating
      dendrite outgrowth/morphogenesis.
    action: ACCEPT
    reason: Consistent with the cytoskeletal/dendritic function and with the IMP dendrite-morphogenesis
      annotation.
    supported_by:
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: 'FUNCTION: Involved in the negative regulation of dendrite outgrowth.'
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: Part of a protein-containing complex (IEA). DPYSL5 forms homotetramers and heterotetramers
      with other DPYS-like (CRMP) proteins.
    action: KEEP_AS_NON_CORE
    reason: Correct but very generic complex term; non-core. The specific oligomerization is better captured
      by the CRMP2 interaction evidence.
    supported_by:
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: Homotetramer, and heterotetramer with other DPYS-like proteins
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Neuronal cell body localization (IEA from ortholog transfer).
    action: KEEP_AS_NON_CORE
    reason: Plausible neuronal localization, consistent with brain-specific cytoplasmic expression; non-core.
    supported_by:
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0045202
    label: synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Synapse (IEA from ortholog transfer).
    action: KEEP_AS_NON_CORE
    reason: Broad neuronal localization; plausible but non-core and electronically inferred.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Glutamatergic synapse (IEA from ortholog transfer / SynGO-style mapping).
    action: KEEP_AS_NON_CORE
    reason: Specific synaptic-type localization by electronic transfer; plausible but non-core, no direct
      experimental support in hand.
- term:
    id: GO:0050774
    label: negative regulation of dendrite morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:33894126
  qualifier: involved_in
  review:
    summary: Negative regulation of dendrite morphogenesis (IMP). Jeanne et al. 2021 showed missense variants
      in DPYSL5 cause a neurodevelopmental disorder (corpus callosum agenesis, cerebellar abnormalities)
      and link DPYSL5 to control of dendrite/neurite outgrowth.
    action: ACCEPT
    reason: Core function with direct mutational (IMP) evidence and matching the UniProt FUNCTION statement.
      This is the best-supported specific role of DPYSL5.
    supported_by:
    - reference_id: PMID:33894126
      supporting_text: Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum
        agenesis and cerebellar abnormalities.
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: 'FUNCTION: Involved in the negative regulation of dendrite outgrowth.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-399944
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS, semaphorin/CRMP signalling reaction).
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with other location annotations.
    supported_by:
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-399947
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS).
    action: ACCEPT
    reason: Correct cytosolic localization (duplicate-by-reaction of the same valid annotation).
    supported_by:
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-399951
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS).
    action: ACCEPT
    reason: Correct cytosolic localization (duplicate-by-reaction of the same valid annotation).
    supported_by:
    - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: TAS
  original_reference_id: PMID:10851247
  qualifier: involved_in
  review:
    summary: Signal transduction (TAS, Inatome et al. 2000). CRAM/CRMP5 associates with CRMP3 and protein-tyrosine
      kinase(s) in developing brain.
    action: KEEP_AS_NON_CORE
    reason: Very broad process term; true in spirit (CRMP signalling) but uninformative and non-core.
    supported_by:
    - reference_id: PMID:10851247
      supporting_text: a novel CRMP3-associated protein, designated CRAM ... associates with CRMP3 and
        protein-tyrosine kinase(s) in the developing rat brain
- term:
    id: GO:0007399
    label: nervous system development
  evidence_type: TAS
  original_reference_id: PMID:10851247
  qualifier: involved_in
  review:
    summary: Nervous system development (TAS). DPYSL5/CRAM is brain-specific and developmentally regulated.
    action: KEEP_AS_NON_CORE
    reason: Correct but broad; non-core relative to the specific dendrite-morphogenesis role.
    supported_by:
    - reference_id: PMID:10851247
      supporting_text: The expression of CRAM is brain-specific, is high in fetal and neonatal rat brain
- term:
    id: GO:0007411
    label: axon guidance
  evidence_type: TAS
  original_reference_id: PMID:10851247
  qualifier: involved_in
  review:
    summary: Axon guidance (TAS). The CRMP family transduces semaphorin-induced growth-cone collapse during
      neural development; CRAM/CRMP5 associates with CRMP3 in this context.
    action: KEEP_AS_NON_CORE
    reason: Genuine CRMP-family process, but DPYSL5's distinguishing, experimentally supported role is
      negative regulation of dendrite morphogenesis; keep axon guidance as a valid non-core process.
    supported_by:
    - reference_id: PMID:10851247
      supporting_text: Four members of collapsin response mediator proteins (CRMPs) are thought to be
        involved in the semaphorin-induced growth cone collapse during neural development
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: MISCITED
    review_notes: Source of the two domain-based IEA hydrolase annotations (GO:0016787, GO:0016810). The
      InterPro2GO mapping fires on the metallo-hydrolase fold but DPYSL5 lacks the catalytic metal site;
      the activity annotations are not supported for this member.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl
    Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10851247
  title: Identification of CRAM, a novel unc-33 gene family protein that associates with CRMP3 and protein-tyrosine
    kinase(s) in the developing rat brain.
  findings:
  - statement: DPYSL5/CRAM is a CRMP-family protein (~57% identical to dihydropyrimidinase, 50-51% to
      CRMPs) that associates with CRMP3 and protein-tyrosine kinases.
    supporting_text: a novel CRMP3-associated protein, designated CRAM ... shows 57% identity with dihydropyrimidinase,
      and shows 50-51% identity with CRMPs
  - statement: Brain-specific expression, highest in fetal/neonatal brain and up-regulated during neuronal
      differentiation.
    supporting_text: The expression of CRAM is brain-specific, is high in fetal and neonatal rat brain
      ... up-regulated during neuronal differentiation
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified primary identification of CRMP5/CRAM; abstract read. Establishes CRMP-family
      membership and neuronal/developmental context.
- id: PMID:33894126
  title: Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis
    and cerebellar abnormalities.
  findings:
  - statement: Missense variants in DPYSL5 cause a neurodevelopmental disorder; DPYSL5 controls dendrite/neurite
      outgrowth.
    supporting_text: Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum
      agenesis and cerebellar abnormalities.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; primary human genetics paper supporting the IMP negative-regulation-of-dendrite-morphogenesis
      annotation.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:29892012
  title: An interactome perturbation framework prioritizes damaging missense mutations for developmental
    disorders.
  findings: []
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the allele frequency
    spectrum in human populations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; supports generic protein binding only.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread
    Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput neurodegenerative-disease interactome; generic protein binding only.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: Reactome:R-HSA-399944
  title: Other semaphorin interactions (CRMP signalling).
  findings: []
- id: Reactome:R-HSA-399947
  title: CRMP phosphorylation / semaphorin signalling reaction.
  findings: []
- id: Reactome:R-HSA-399951
  title: CRMP signalling reaction.
  findings: []
- id: file:human/DPYSL5/DPYSL5-uniprot.txt
  title: UniProt entry Q9BPU6 (DPYSL5)
  findings:
  - statement: DPYSL5 lacks the metal-cofactor-binding residues essential for dihydropyrimidinase activity.
    supporting_text: Lacks most of the conserved residues that are essential for binding the metal cofactor
      and hence for dihydropyrimidinase activity.
  - statement: DPYSL5 belongs to the metallo-dependent hydrolase superfamily and negatively regulates
      dendrite outgrowth.
    supporting_text: Belongs to the metallo-dependent hydrolases superfamily.
aliases:
- CRMP5
- CRAM
- DRP-5
- DRP5
- ULIP-6
- ULIP6
- CRMP3-associated molecule
- Collapsin response mediator protein 5
core_functions:
- description: Catalytically inactive CRMP-family cytoskeletal regulator that negatively regulates dendrite/neurite
    outgrowth and morphogenesis during neuronal development. Acts within the semaphorin/collapsin growth-cone
    signalling system and through homo- and hetero-oligomerization with other CRMPs (notably DPYSL2/CRMP2);
    it has lost the ancestral dihydropyrimidinase activity of the family.
  directly_involved_in:
  - id: GO:0050774
    label: negative regulation of dendrite morphogenesis
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0030425
    label: dendrite
  supported_by:
  - reference_id: PMID:33894126
    supporting_text: Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum
      agenesis and cerebellar abnormalities.
  - reference_id: file:human/DPYSL5/DPYSL5-uniprot.txt
    supporting_text: 'FUNCTION: Involved in the negative regulation of dendrite outgrowth.'
suggested_questions:
- question: Does DPYSL5/CRMP5 retain any residual or neofunctionalized enzymatic activity, or is it strictly
    a non-catalytic scaffold? The UniProt CAUTION asserts loss of dihydropyrimidinase activity, but no
    assay has excluded all hydrolase activities.
- question: What is the molecular mechanism by which DPYSL5 negatively regulates dendrite outgrowth -
    does it antagonize CRMP2 (DPYSL2) within hetero-oligomers, and is this mediated through microtubule
    dynamics?
suggested_experiments:
- hypothesis: DPYSL5 has no metallo-hydrolase activity of any kind, consistent with loss of the metal-binding
    site.
  description: Express and purify recombinant DPYSL5 and assay a panel of amidohydrolase/C-N hydrolase
    substrates (including dihydropyrimidinase substrates) with and without divalent metal supplementation;
    compare to active DPYS as a positive control.
- hypothesis: DPYSL5 negatively regulates dendrite outgrowth by antagonizing CRMP2 in hetero-oligomers.
  description: Test dendrite outgrowth in neurons co-expressing DPYSL5 and CRMP2 variants that disrupt
    hetero-oligomerization, quantifying dendrite number/length.