id: Q6U1J5 gene_symbol: col1a1a product_type: PROTEIN status: DRAFT taxon: id: NCBITaxon:7955 label: Danio rerio description: >- col1a1a (collagen type I alpha 1a; the chihuahua locus) encodes the pro-alpha1(I) chain of zebrafish type I collagen, the main fibrillar collagen of bone, skin, scales, tendons and ligaments. It is one of two zebrafish co-orthologs of human COL1A1 that arose in the teleost-specific genome duplication; its paralog col1a1b encodes the teleost alpha3(I) chain. The 1447-aa secreted procollagen has the fibrillar collagen architecture of a signal peptide, an N-propeptide with a von Willebrand factor type C domain, an uninterrupted Gly-X-Y triple-helical domain and a C-terminal fibrillar collagen NC1 (C-propeptide) domain that drives chain recognition and trimer assembly. Its product associates with alpha2(I) (col1a2) and alpha3(I) (col1a1b) chains into type I collagen trimers that self-assemble into banded fibrils of the extracellular matrix; in adult bone, skin and scales the three chains occur at about equal amounts. col1a1a is co-expressed with col1a1b and col1a2 in osteoblasts, tendon and ligament fibroblasts, myosepta and basal epidermis, but it is the only type I collagen gene expressed in the median fin fold and pectoral fin margin, where alpha1(I) homotrimers contribute to actinotrichia. Loss of col1a1a is lethal in larvae (uninflated swim bladder, absent actinotrichia), and dominant glycine substitutions (chihuahua, dmh13, dmh14) cause osteogenesis imperfecta-like short stature, fractures, vertebral deformities and abnormal mineralization, and disrupt fin development and regeneration. existing_annotations: - term: id: GO:0001501 label: skeletal system development evidence_type: IMP original_reference_id: PMID:28835471 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-180503-6 review: summary: >- Genotype col1a1a^dmh13/+ (ZFIN). dmh13 is a dominant glycine substitution (G1093R) in the col1a1a triple helix, isolated in an adult forward screen for short stature, with vertebral deformation and excessive bone formation. action: ACCEPT reason: >- Type I collagen is the main organic component of bone matrix, and dominant helix glycine substitutions in the col1a1a chain produce skeletal dysplasia, as in human COL1A1-related osteogenesis imperfecta. The col1a1a chain contributes structure to the skeletal matrix, so this is a direct role, and human COL1A1 carries the same term by IMP. supported_by: - reference_id: PMID:28835471 supporting_text: Both the dmh13 and dmh14 mutants carry mutations in the col1a1a gene (G1093R; G1144E), which are closely linked, while the dmh29 mutants exhibit mutations in a glycine residue of the col1a1b gene (G1123D), leading to a very similar phenotype. - term: id: GO:0001501 label: skeletal system development evidence_type: IMP original_reference_id: PMID:28835471 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-180504-3 review: summary: >- Genotype col1a1a^dmh14/+ (G1144E), the second dominant col1a1a allele from the same adult screen, with the same short-stature and vertebral phenotype class. action: ACCEPT reason: >- As for dmh13: a dominant helix glycine substitution in the col1a1a chain disrupts skeletal development, consistent with the structural role of type I collagen in bone. supported_by: - reference_id: PMID:28835471 supporting_text: Interestingly, in this phenotypic class, we were able to identify dominant mutations in all components of Collagen I - term: id: GO:0001501 label: skeletal system development evidence_type: IMP original_reference_id: PMID:30082390 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-110630-21 review: summary: >- Genotype col1a1a^dc124/+ (chihuahua). In the micro-CT phenomic survey, chi/+ fish have short stature, kyphoscoliosis, vertebral malformation and fractures, modelling moderate-to-severe dominant osteogenesis imperfecta. action: ACCEPT reason: >- Direct evidence from a col1a1a allele that the alpha1(I) chain is required for normal skeletal development; the chain supplies the collagen framework of bone. supported_by: - reference_id: PMID:30082390 supporting_text: The col1a1achi/+ mutant, reported earlier (21, 35), carries the same mutation that was identified in a human patient with severe and heavily deforming OI type III (34), and also displays a moderate to severe phenotype with skeletal malformation, including shorter vertebral bodies, kyphoscoliosis, and evidence of fractures - term: id: GO:0001501 label: skeletal system development evidence_type: IMP original_reference_id: PMID:30082390 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-180503-6 review: summary: >- Genotype col1a1a^dmh13/+, re-examined by micro-CT phenomics in the type I collagen mutant survey. action: ACCEPT reason: >- A col1a1a allele with a skeletal phenotype; same reasoning as the PMID:28835471 row for this allele. supported_by: - reference_id: PMID:30082390 supporting_text: The col1a1admh13, col1a1admh14, col1a1bdmh29, and col1a2dmh15 mutant fish were generated in a forward genetics screen (40). - term: id: GO:0001501 label: skeletal system development evidence_type: IMP original_reference_id: PMID:30082390 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-180503-7 review: summary: >- The supporting genotype of this row, ZDB-GENO-180503-7, is col1a1b^dmh29/+ (ZFIN genotype page, checked 2026-09-28). It carries a col1a1b allele and no col1a1a lesion; in the paper, dmh29 is listed as an alpha3(I) (col1a1b) glycine substitution. action: ACCEPT reason: >- The claim is true: the rows backed by col1a1a alleles (dc124, dmh13, dmh14, sa1748) are ACCEPTed for this term. This row's evidence is a col1a1b mutant, so it is attached to the wrong gene; that is recorded in source_defects, not grounds for REMOVE, which judges the claim. The same evidence belongs on col1a1b, which already carries skeletal system development IMP for this genotype from PMID:28835471. supported_by: - reference_id: PMID:28835471 supporting_text: Both the dmh13 and dmh14 mutants carry mutations in the col1a1a gene (G1093R; G1144E), which are closely linked - reference_id: PMID:28835471 supporting_text: Analysis by microcomputed tomography (μCT) revealed strong deformations of the vertebrae, especially of the hemal and neural arches source_defects: - defect_type: WRONG_GENE_PRODUCT resource: ZFIN slot: DB_Object_ID requested_change: REPOINT asserted_value: UniProtKB:Q6U1J5 corrected_value: UniProtKB:Q6PEI9 corrected_label: col1a1b confidence: CONFIRMED explanation: The supporting genotype ZDB-GENO-180503-7 is col1a1b^dmh29/+, a col1a1b glycine substitution with no col1a1a lesion, so the annotation belongs on col1a1b. supported_by: - reference_id: PMID:30082390 supporting_text: and col1a1achi/+), α2(I) (col1a2dmh15/+), or α3(I) (col1a1bdmh29/+). - reference_id: PMID:28835471 supporting_text: while the dmh29 mutants exhibit mutations in a glycine residue of the col1a1b gene (G1123D) - term: id: GO:0001501 label: skeletal system development evidence_type: IMP original_reference_id: PMID:30082390 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-180503-8 review: summary: >- The supporting genotype of this row, ZDB-GENO-180503-8, is col1a2^dmh15/+ (ZFIN genotype page, checked 2026-09-28): an alpha2(I) glycine substitution, with no col1a1a lesion. action: ACCEPT reason: >- The claim is true: the rows backed by col1a1a alleles are ACCEPTed for this term. This row's evidence is a col1a2 mutant, so it is attached to the wrong gene; that is recorded in source_defects, not grounds for REMOVE, which judges the claim. supported_by: - reference_id: PMID:28835471 supporting_text: Both the dmh13 and dmh14 mutants carry mutations in the col1a1a gene (G1093R; G1144E), which are closely linked - reference_id: PMID:28835471 supporting_text: Analysis by microcomputed tomography (μCT) revealed strong deformations of the vertebrae, especially of the hemal and neural arches source_defects: - defect_type: WRONG_GENE_PRODUCT resource: ZFIN slot: DB_Object_ID requested_change: CHECK asserted_value: UniProtKB:Q6U1J5 confidence: CONFIRMED explanation: The supporting genotype ZDB-GENO-180503-8 is col1a2^dmh15/+, an alpha2(I) glycine substitution with no col1a1a lesion, so the annotation belongs on col1a2 (whose accession this review does not establish). supported_by: - reference_id: PMID:28835471 supporting_text: In these mutants, we detected a mutant-specific nonsynonymous mutation in col1a2 (G882D) linked to the phenotype. - term: id: GO:0001501 label: skeletal system development evidence_type: IMP original_reference_id: PMID:30082390 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-180504-3 review: summary: >- Genotype col1a1a^dmh14/+, re-examined by micro-CT phenomics. action: ACCEPT reason: >- A col1a1a allele with a skeletal phenotype; same reasoning as the PMID:28835471 row for this allele. supported_by: - reference_id: PMID:30082390 supporting_text: The alleles dmh13, dmh14, and dmh29 all cluster in the major ligand binding region 3 of type I collagen - term: id: GO:0001501 label: skeletal system development evidence_type: IMP original_reference_id: PMID:30082390 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-190402-1 review: summary: >- Genotype col1a1a^sa1748/+; col1a1b^sa12931/+ (double heterozygous nonsense alleles). Either single heterozygote is normal, but the double heterozygote has a mild osteogenesis imperfecta type I-like phenotype with rib fractures, scoliosis and vertebral compression. action: ACCEPT reason: >- Valid evidence for both paralogs: the phenotype appears only when the combined dose of alpha1(I) and alpha3(I) is reduced. This is the key evidence that the two chains act together, and partly interchangeably, in bone collagen. supported_by: - reference_id: PMID:30082390 supporting_text: Hence, we generated a double-heterozygous knockout mutant (col1a1a+/−;col1a1b+/−), which displays a mild skeletal phenotype, with a low frequency of spontaneous fractures (calluses in the ribs), scoliosis and localized compression, fusions, and mild malformation of the vertebral bodies in some of the mutant fish - term: id: GO:0005201 label: extracellular matrix structural constituent evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: >- InterPro2GO/UniRule mapping from the fibrillar collagen C-terminal domain (IPR000885). action: ACCEPT reason: >- Correct but general. The more specific child GO:0030020 (conferring tensile strength) is present by IBA and is used in core_functions. A broader IEA is acceptable alongside it. supported_by: - reference_id: PMID:26876635 supporting_text: As collagen type I is the major structural protein in bone and skin - term: id: GO:0005576 label: extracellular region evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: >- Automated location from ARBA/UniRule; the procollagen has a signal peptide and is secreted. action: ACCEPT reason: >- Correct, if general; the specific location is the extracellular matrix (GO:0031012, IBA). supported_by: - reference_id: PMID:26876635 supporting_text: Following secretion, specific peptidases are responsible for the removal of the N- and C-propeptides, allowing the mature triple helix to self-assemble into fibrils. - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - PANTHER:PTN002771199 - ZFIN:ZDB-GENE-030131-9102 review: summary: >- IBA from PTN002771199, whose only listed experimental source is col1a1a itself (ZFIN:ZDB-GENE-030131-9102), i.e. the IDA cytoplasm row from PMID:19757382 reviewed below. action: REMOVE reason: >- The node's only grounding is an mRNA in situ hybridization in which col1a1 was used as a keratinocyte marker. mRNA localization does not show where the protein acts. Type I collagen chains act in the extracellular matrix. The procollagen passes through the endoplasmic reticulum lumen during synthesis, but that is not where its structural activity is exerted, so "is active in cytoplasm" misplaces the function. No fibrillar collagen in the family has experimental evidence of cytoplasmic activity to support placing this at an ancestral node. propagation_review: root_cause: SOURCE_BAD failure_modes: - SOURCE_EVIDENCE_WEAK - COMPARTMENT_OR_COMPLEX_MISMATCH source_entities: - source_id: PANTHER:PTN002771199 source_label: PTN002771199 source_status: SOURCE_WEAK_OR_INFERRED comment: The node's only listed experimental source is zebrafish col1a1a itself, so the IBD rests on a single mRNA-level observation. - source_id: ZFIN:ZDB-GENE-030131-9102 source_label: col1a1a source_status: SOURCE_BAD comment: Source IDA (PMID:19757382) is a col1a1 mRNA in situ used as a keratinocyte marker, not a protein localization; the protein acts in the extracellular matrix. supported_by: - reference_id: PMID:19757382 supporting_text: double fluorescent in situ hybridizations for grhl1 and the keratinocyte markers collagen 1a1 - reference_id: PMID:26876635 supporting_text: In the endoplasmic reticulum, type I collagen is synthesized as a pro-collagen molecule - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:19757382 qualifier: located_in review: summary: >- The paper is about grhl1-expressing epidermal cell lineages. The full text was read. col1a1 appears only as an mRNA probe marking basal keratinocytes in double fluorescent in situ hybridization. No col1a1 protein localization is reported. action: MARK_AS_OVER_ANNOTATED reason: >- The staining localizes col1a1 transcripts, not the protein. The claim is not strictly false: nascent procollagen sits in the endoplasmic reticulum, which GO places within the cytoplasm. But it is uninformative about where the protein acts, and it has been propagated by IBA to both paralogs. The informative location is the extracellular matrix. Marked as over-annotated rather than removed, because the figures could not be inspected. supported_by: - reference_id: PMID:19757382 supporting_text: double fluorescent in situ hybridizations for grhl1 and the keratinocyte markers collagen 1a1 - term: id: GO:0030020 label: extracellular matrix structural constituent conferring tensile strength evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables supporting_entities: - PANTHER:PTN001166351 - UniProtKB:P02462 - WB:WBGene00002280 review: summary: >- Phylogenetic propagation of the core molecular function of fibrillar and network collagens. action: ACCEPT reason: >- This is the core molecular function of a type I collagen chain. Loss of alpha1(I) is lethal and removes actinotrichia, and the chain is a major component of bone, skin and scale collagen. supported_by: - reference_id: PMID:26876635 supporting_text: We demonstrated that, both in zebrafish embryos and adult tissues, three instead of two types of alpha chains contribute to the formation of the collagen type I triple helix - reference_id: PMID:30082390 supporting_text: Eventually, all genotypes containing a homozygous knockout of col1a1a [loss of α1(I)] were found to be lethal by the age of 3 mo. - term: id: GO:0030199 label: collagen fibril organization evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:88452 - MGI:MGI:88453 - MGI:MGI:88458 - PANTHER:PTN009074843 - RGD:61817 - RGD:621351 - UniProtKB:P02458 - UniProtKB:P02461 - UniProtKB:P05997 - UniProtKB:P08123 - ZFIN:ZDB-GENE-030131-9102 review: summary: >- IBA for fibrillar collagen chains. col1a1a is among the sources, via its own IMP from PMID:35282456; this is expected, not circular. action: ACCEPT reason: >- Fibrillar collagen chains are the building blocks of the fibrils. The chain does part of the work of fibril organization (the structure case), and chihuahua shows abnormal fibril packing. supported_by: - reference_id: PMID:26876635 supporting_text: allowing the mature triple helix to self-assemble into fibrils - term: id: GO:0030199 label: collagen fibril organization evidence_type: IMP original_reference_id: PMID:35282456 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-221115-1 review: summary: >- Chihuahua (col1a1a^dc124/+). Transmission electron microscopy shows densely packed collagen fibrils next to osteoblasts, instead of the loosely arranged fibrils of normal osteoid. A low-phosphorus diet partly restores fibril organization. action: ACCEPT reason: >- Direct ultrastructural evidence that a structurally abnormal alpha1(I) chain alters the organization of the fibrils it builds. supported_by: - reference_id: PMID:35282456 supporting_text: In contrast, the Chi/+ bone matrix is characterised by densely packed collagen fibrils in the vicinity of the osteoblasts (Figure 7C). - term: id: GO:0030278 label: regulation of ossification evidence_type: IMP original_reference_id: PMID:14623232 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-011017-1 review: summary: >- Original description of chihuahua (dc124), a dominant col1a1a mutation found by radiographic screening, which causes a general defect in bone growth resembling osteogenesis imperfecta. Abstract only. action: MODIFY reason: >- The mutant phenotype (a general defect in bone growth) supports a role for col1a1a in ossification. But the alpha1(I) chain acts as the structural organic matrix of bone, not as a regulator that modulates the rate or extent of ossification. The regulatory term implies a mechanism the evidence does not show. Replace with the parent process, ossification, keeping the acts_upstream_of_or_within qualifier. proposed_replacement_terms: - id: GO:0001503 label: ossification supported_by: - reference_id: PMID:14623232 supporting_text: We have isolated chihuahua, a dominant mutation causing a general defect in bone growth. - reference_id: PMID:14623232 supporting_text: Mapping and molecular characterization of the chihuahua mutation indicates that the defect resides in the gene encoding the collagen I(alpha1) chain. - term: id: GO:0030282 label: bone mineralization evidence_type: IMP original_reference_id: PMID:35282456 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-221115-1 review: summary: >- Chihuahua bone is overmineralized. Reducing dietary phosphorus lowers mineral content and partly rescues the phenotype. action: KEEP_AS_NON_CORE reason: >- Collagen I fibrils are the template on which bone mineral is deposited, and an abnormal chain alters mineralization. This is a real but downstream consequence of the structural function, so it is kept as non-core. supported_by: - reference_id: PMID:35282456 supporting_text: Altered collagen structure and excess mineralisation are the main causes for the bone phenotype. - term: id: GO:0031012 label: extracellular matrix evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - FB:FBgn0000299 - FB:FBgn0016075 - MGI:MGI:104687 - MGI:MGI:104688 - MGI:MGI:1858212 - MGI:MGI:2152695 - MGI:MGI:2672118 - MGI:MGI:2685312 - MGI:MGI:88445 - MGI:MGI:88446 - MGI:MGI:88449 - MGI:MGI:88451 - MGI:MGI:88452 - MGI:MGI:88453 - MGI:MGI:88454 - MGI:MGI:88455 - MGI:MGI:88456 - MGI:MGI:88457 - MGI:MGI:88462 - MGI:MGI:88463 - MGI:MGI:88467 - MGI:MGI:88468 - PANTHER:PTN008390299 - RGD:2372 - RGD:2374 - RGD:61817 - RGD:621351 - RGD:70922 - RGD:71029 - UniProtKB:P02458 - UniProtKB:P02461 - UniProtKB:P02462 - UniProtKB:P02467 - UniProtKB:P05997 - UniProtKB:P08123 - UniProtKB:P08572 - UniProtKB:P12107 - UniProtKB:P20849 - UniProtKB:P20908 - UniProtKB:P29400 - UniProtKB:P53420 - UniProtKB:Q01955 - UniProtKB:Q03692 - UniProtKB:Q14031 - UniProtKB:Q14050 - UniProtKB:Q14055 - UniProtKB:Q7SIB2 - WB:WBGene00000527 - WB:WBGene00001263 - WB:WBGene00002280 review: summary: >- Deep collagen-family IBA for extracellular matrix, the site of action of all collagen chains. action: ACCEPT reason: >- Correct and appropriately specific. Type I collagen is extracted from the matrix of zebrafish bone, skin and scales. supported_by: - reference_id: PMID:26876635 supporting_text: In conclusion, we provided a deep molecular and biochemical characterization of zebrafish collagen type I, the most abundant extracellular matrix protein in bone and skin. - term: id: GO:0031101 label: fin regeneration evidence_type: IMP original_reference_id: PMID:21420398 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-110630-21 review: summary: >- Chihuahua (col1a1a^dc124/+) shows aberrant actinotrichia and lepidotrichia during fin regeneration. Abstract only. action: KEEP_AS_NON_CORE reason: >- Plausible and consistent with col1a1a being the type I collagen gene of actinotrichia-forming cells. It is a context-specific use of the structural function, so non-core. Deferred to the curator, who read the full text. supported_by: - reference_id: PMID:21420398 supporting_text: The col1a1 dominant mutant chihuahua showed aberrant phenotypes in both actinotrichia and lepidotrichia during fin development and regeneration. - term: id: GO:0033333 label: fin development evidence_type: IMP original_reference_id: PMID:9007245 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-111013-8 review: summary: >- Genotype col1a1a^tt281/tt281 (ZFIN), a recessive allele from the Tuebingen large-scale screen for fin formation mutants (abstract only; the allele is not named in the abstract). action: ACCEPT reason: >- Fin fold development is a copy-specific role of col1a1a. It is the only type I collagen gene expressed in the median fin fold and pectoral fin margin. Actinotrichia, the collagen fibres that support the fin fold, are absent in col1a1a knockout larvae and are thought to contain alpha1(I) homotrimers. This role is not shared with col1a1b, so it is accepted as part of the col1a1a-specific function. Deferred to the curator for the allele-level details. supported_by: - reference_id: PMID:9007245 supporting_text: Mutations in 11 genes lead to abnormal morphology or degeneration of both caudal and pectoral fin folds. - reference_id: PMID:30082390 supporting_text: Upon detailed examination of the finfold, these actinotrichia were found to be absent in col1a1a−/− mutant larvae (Fig. 5D). - term: id: GO:0033334 label: fin morphogenesis evidence_type: IMP original_reference_id: PMID:21420398 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-110630-21 review: summary: >- Chihuahua (col1a1a^dc124/+) has abnormal actinotrichia and lepidotrichia during fin development. col1a1a is expressed in actinotrichia-forming cells. action: ACCEPT reason: >- The alpha1(I) chain is a structural component of actinotrichia, the fibres that shape the fin fold, so col1a1a contributes structure to fin morphogenesis. This is the copy-specific part of the col1a1a function. supported_by: - reference_id: PMID:21420398 supporting_text: Both col1a1a and col2a1b were found in actinotrichia forming cells. - reference_id: PMID:26876635 supporting_text: Interestingly, only col1a1a was shown to be expressed in the median fin fold and in the apical ectodermal ridge of the pectoral fin at 48, 72 and 96 hpf - term: id: GO:0033339 label: pectoral fin development evidence_type: IMP original_reference_id: PMID:21420398 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-110630-1 review: summary: >- Morpholino knockdown (MO2-col1a1a) disrupts actinotrichia and fin fold morphogenesis. Abstract only. action: KEEP_AS_NON_CORE reason: >- Morphant-only evidence, but consistent with the germline knockout, whose larvae have frilly pectoral fin margins and lack actinotrichia. Kept as a more specific, non-core instance of the fin role. supported_by: - reference_id: PMID:21420398 supporting_text: Morpholino knockdown in zebrafish embryos demonstrated that the two collagens and lh1 are essential for actinotrichia and fin fold morphogenesis. - reference_id: PMID:30082390 supporting_text: Furthermore, the distal margins of the pectoral fins, and the finfold, were shown to be ruffled in these mutants - term: id: GO:0035630 label: bone mineralization involved in bone maturation evidence_type: IMP original_reference_id: PMID:29665086 qualifier: acts_upstream_of_or_within review: summary: >- Multiscale analysis of chihuahua bone shows a higher degree of mineralization and lower collagen and mineral maturity. Abstract only. action: KEEP_AS_NON_CORE reason: >- A real downstream effect of an abnormal collagen template on mineral deposition. Non-core for a structural matrix protein. Deferred to the curator on the precise child term. supported_by: - reference_id: PMID:29665086 supporting_text: At the tissue level, Chi/+ displayed a higher degree of mineralization, lower collagen maturity, lower mineral maturity, altered osteoblast morphology, and lower osteocyte lacunar density compared to wild-type zebrafish. - term: id: GO:0043588 label: skin development evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:88453 - MGI:MGI:88467 - PANTHER:PTN002770836 - UniProtKB:P02461 review: summary: >- IBA from a node holding the COL1A1 and COL3A1 clade, based on mammalian skin phenotypes. action: KEEP_AS_NON_CORE reason: >- col1a1a is expressed in the basal epidermis, and type I collagen is a major skin collagen in zebrafish. The structural contribution to dermal matrix supports inheriting the term, but no zebrafish skin phenotype has been reported for col1a1a, so it is non-core. supported_by: - reference_id: PMID:26876635 supporting_text: At every time point, expression of all three genes could be detected in the epidermis. - term: id: GO:0046849 label: bone remodeling evidence_type: IMP original_reference_id: PMID:29665086 qualifier: acts_upstream_of_or_within review: summary: >- Chihuahua bone quality study (abstract only). The abstract reports altered osteoblast morphology and osteocyte density but does not mention remodeling. action: KEEP_AS_NON_CORE reason: >- The effect on remodeling is at best indirect: the abnormal collagen matrix is what osteoclasts and osteoblasts turn over, and col1a1a performs no step of resorption or reactive formation. The acts_upstream_of_or_within qualifier fits such an indirect effect, and the full text was not available, so the row is kept as non-core rather than removed. supported_by: - reference_id: PMID:29665086 supporting_text: The alterations in the cellular, compositional, and structural properties of Chi/+ bones bear an explanation for the impaired local mechanical properties - term: id: GO:0046849 label: bone remodeling evidence_type: IMP original_reference_id: PMID:35282456 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-221115-1 review: summary: >- Chihuahua vertebrae show compression fractures with repair and abundant osteoclast (TRAP) activity compared with wild type. action: KEEP_AS_NON_CORE reason: >- The increased osteoclast activity is a response to fractures and to the abnormal matrix. It is an indirect consequence of the structural defect, not a step of remodeling performed by the collagen chain. Kept as non-core under the acts_upstream_of_or_within qualifier. supported_by: - reference_id: PMID:35282456 supporting_text: Both Chi/+ and Chi/+LP show abundant osteoclast activity compared to WT. - term: id: GO:0048705 label: skeletal system morphogenesis evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:88453 - MGI:MGI:88467 - PANTHER:PTN002770836 review: summary: >- IBA from the COL1A1/COL3A1 node, based on mouse skeletal phenotypes. action: KEEP_AS_NON_CORE reason: >- Consistent with the zebrafish mutant phenotypes: vertebral malformation and shorter vertebral bodies in chihuahua and in dmh13 and dmh14. The broader skeletal system development term already covers this role, so this one is kept as non-core. supported_by: - reference_id: PMID:28835471 supporting_text: Analysis by microcomputed tomography (μCT) revealed strong deformations of the vertebrae, especially of the hemal and neural arches - term: id: GO:0005584 label: collagen type I trimer evidence_type: IDA original_reference_id: PMID:26876635 review: summary: >- Proposed location. Mass spectrometry of pepsin-extracted type I collagen from 48 hpf embryos and from adult bone, skin and scales identifies alpha1(I) peptides together with alpha3(I) and alpha2(I). Amino acid analysis excludes significant homotrimers in adult tissues and supports about equal amounts of the three chains. action: NEW reason: >- This is the complex the alpha1(I) chain is a subunit of. Human COL1A1 carries GO:0005584 by IDA/IPI/IMP. By definition the term covers both heterotrimers and alpha1(I) homotrimers, which also fits the proposed homotrimers in actinotrichia. The same term is proposed for col1a1b. supported_by: - reference_id: PMID:26876635 supporting_text: We demonstrated that, both in zebrafish embryos and adult tissues, three instead of two types of alpha chains contribute to the formation of the collagen type I triple helix - reference_id: PMID:26876635 supporting_text: >- a 1:1:1 ratio for the three α chains in all tissues is inferred core_functions: - description: >- Col1a1a (alpha1(I)) is a structural chain of zebrafish type I collagen. It assembles with alpha2(I) (col1a2) and the teleost alpha3(I) (col1a1b) into triple-helical trimers that are secreted and self-assemble into fibrils. These fibrils give tensile strength to the matrix of bone, skin, scales, tendons and ligaments, and serve as the template for bone mineralization. alpha1(I) is the dose-limiting chain: its complete loss is lethal, whereas loss of alpha3(I) is tolerated. molecular_function: id: GO:0030020 label: extracellular matrix structural constituent conferring tensile strength directly_involved_in: - id: GO:0030199 label: collagen fibril organization - id: GO:0001501 label: skeletal system development locations: - id: GO:0031012 label: extracellular matrix in_complex: id: GO:0005584 label: collagen type I trimer supported_by: - reference_id: PMID:26876635 supporting_text: We demonstrated that, both in zebrafish embryos and adult tissues, three instead of two types of alpha chains contribute to the formation of the collagen type I triple helix - reference_id: PMID:30082390 supporting_text: Eventually, all genotypes containing a homozygous knockout of col1a1a [loss of α1(I)] were found to be lethal by the age of 3 mo. - reference_id: PMID:35282456 supporting_text: In contrast, the Chi/+ bone matrix is characterised by densely packed collagen fibrils in the vicinity of the osteoblasts (Figure 7C). - description: >- Copy-specific role: col1a1a is the only type I collagen gene expressed in the median fin fold and pectoral fin margin. There its product, thought to form alpha1(I) homotrimers, is a structural component of actinotrichia, the collagen fibres that support and shape the larval fin fold and the tip of adult fin rays. Actinotrichia are absent in col1a1a knockout larvae. molecular_function: id: GO:0030020 label: extracellular matrix structural constituent conferring tensile strength directly_involved_in: - id: GO:0033334 label: fin morphogenesis in_complex: id: GO:0005584 label: collagen type I trimer supported_by: - reference_id: PMID:26876635 supporting_text: Given the absence of col1a1b and col1a2 expression, our findings also support the presence of α1(I) homotrimers in actinotrichia. - reference_id: PMID:30082390 supporting_text: Upon detailed examination of the finfold, these actinotrichia were found to be absent in col1a1a−/− mutant larvae (Fig. 5D). - reference_id: PMID:21420398 supporting_text: Both col1a1a and col2a1b were found in actinotrichia forming cells. suggested_questions: - question: >- ZFIN attaches two col1a1a skeletal system development IMP rows (PMID:30082390) to genotypes that carry no col1a1a allele (col1a1b^dmh29/+ and col1a2^dmh15/+). Should these rows move to col1a1b and col1a2? col1a1b currently has no annotation from PMID:30082390 at all. - question: >- Is col1a1b (alpha3(I)) upregulated in col1a1a heterozygous nonsense mutants (transcriptional adaptation)? This would help explain why col1a1a+/- fish have no skeletal phenotype. - question: >- Do actinotrichia really contain alpha1(I) homotrimers? The inference rests on in situ expression and co-migration, not on direct chain analysis of isolated actinotrichia. suggested_experiments: - description: >- Chain-specific proteomics (SRM with alpha1(I)- and alpha3(I)-unique peptides) of isolated actinotrichia and of adult bone, skin and scale collagen from col1a1a+/- and col1a1b-/- fish, to measure trimer composition and any compensatory change in the other chain. experiment_type: targeted mass spectrometry - description: >- Compare col1a1a nonsense (NMD) alleles with a promoter-deletion (RNA-less) col1a1a allele and quantify col1a1b expression, to separate transcriptional adaptation from true redundancy. experiment_type: genetic loss-of-function comparison references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:14623232 title: Radiographic analysis of zebrafish skeletal defects. findings: - statement: chihuahua is a dominant col1a1a allele causing a general defect in bone growth resembling osteogenesis imperfecta. supporting_text: Heterozygous chihuahua fish have phenotypic similarities to human osteogenesis imperfecta reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only. Matches UniProt RN [1] for Q6U1J5 (EMBL AAR24536, "Chihuahua"). - id: PMID:19757382 title: Zebrafish grainyhead-like1 is a common marker of different non-keratinocyte epidermal cell lineages, which segregate from each other in a Foxi3-dependent manner. findings: - statement: col1a1 is used only as an mRNA marker of basal keratinocytes; no protein localization is reported. supporting_text: double fluorescent in situ hybridizations for grhl1 and the keratinocyte markers collagen 1a1 reference_review: relevance: LOW correctness: MISCITED review_notes: Full text read. Supports col1a1a mRNA expression in basal keratinocytes, not protein localization to cytoplasm (the GOA IDA claim). - id: PMID:21420398 title: Actinotrichia collagens and their role in fin formation. findings: - statement: col1a1a is expressed in actinotrichia-forming cells and is required for actinotrichia and fin fold morphogenesis. supporting_text: Morpholino knockdown in zebrafish embryos demonstrated that the two collagens and lh1 are essential for actinotrichia and fin fold morphogenesis. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only. Establishes the copy-specific fin role of col1a1a. - id: PMID:28835471 title: 'Genetic Screen for Postembryonic Development in the Zebrafish (Danio rerio): Dominant Mutations Affecting Adult Form.' findings: - statement: dmh13 and dmh14 are dominant col1a1a glycine substitutions, and dmh29 is a col1a1b glycine substitution, all with short stature and vertebral defects. supporting_text: Both the dmh13 and dmh14 mutants carry mutations in the col1a1a gene (G1093R; G1144E), which are closely linked, while the dmh29 mutants exhibit mutations in a glycine residue of the col1a1b gene (G1123D), leading to a very similar phenotype. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text. Alleles checked against ZFIN genotype pages. - id: PMID:29665086 title: Severely Impaired Bone Material Quality in Chihuahua Zebrafish Resembles Classical Dominant Human Osteogenesis Imperfecta. findings: - statement: Chihuahua bone is hypermineralized with lower collagen maturity. supporting_text: At the tissue level, Chi/+ displayed a higher degree of mineralization, lower collagen maturity, lower mineral maturity reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract only. - id: PMID:30082390 title: Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies. findings: - statement: Single heterozygous col1a1a or col1a1b knockouts are normal; the double heterozygote has a mild OI-like phenotype. supporting_text: Heterozygous loss of either α1(I) or α3(I) did not induce any skeletal abnormalities, while reduced levels of both α1(I) and α3(I) (col1a1a+/−;col1a1b+/− mutants) causes a mild skeletal phenotype with increased bone fragility, arguing for interchangeability and functional redundancy between α1(I) and the homologous α3(I). - statement: Complete loss of col1a1a is lethal; complete loss of col1a1b is viable. supporting_text: Complete loss of the α1(I) chain causes lethality after 7 dpf, while loss of α3(I) only shows increased early lethality if the amount of α1(I) is also diminished. - statement: col1a1a knockout larvae lack actinotrichia. supporting_text: Upon detailed examination of the finfold, these actinotrichia were found to be absent in col1a1a−/− mutant larvae (Fig. 5D). reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text. The key paper testing both paralogs genetically. - id: PMID:35282456 title: Compression Fractures and Partial Phenotype Rescue With a Low Phosphorus Diet in the Chihuahua Zebrafish Osteogenesis Imperfecta Model. findings: - statement: Chihuahua bone matrix has densely packed collagen fibrils and increased osteoclast activity. supporting_text: In contrast, the Chi/+ bone matrix is characterised by densely packed collagen fibrils in the vicinity of the osteoblasts (Figure 7C). reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text. - id: PMID:9007245 title: Genetic analysis of fin formation in the zebrafish, Danio rerio. findings: - statement: Large-scale screen identifying fin fold mutants, including (per ZFIN) the col1a1a allele tt281. supporting_text: Mutations in 11 genes lead to abnormal morphology or degeneration of both caudal and pectoral fin folds. reference_review: relevance: MEDIUM correctness: UNVERIFIED review_notes: Abstract only; the col1a1a allele is not named in the abstract. The genotype link (col1a1a^tt281) is from ZFIN. - id: PMID:26876635 title: 'Zebrafish Collagen Type I: Molecular and Biochemical Characterization of the Major Structural Protein in Bone and Skin.' findings: - statement: Three type I collagen chains (alpha1, alpha2, alpha3) are present at the protein level in embryos and adult bone, skin and scales, at about 1:1:1. supporting_text: Even though in adult bone, skin and scales equal amounts of α1(I), α3(I) and α2(I) chains are present - statement: col1a1a, col1a1b and col1a2 are co-expressed, except that only col1a1a is expressed in the fin fold. supporting_text: Interestingly, only col1a1a was shown to be expressed in the median fin fold and in the apical ectodermal ridge of the pectoral fin at 48, 72 and 96 hpf - statement: alpha1(I) and alpha3(I) share 78% identity; alpha3(I) lacks one inter-chain C-propeptide cysteine. supporting_text: Interestingly, in proα3 this latter domain, crucial for chain association in the trimer, lacks one of the 4 conserved cysteine residues involved in inter-chain bonds (Cys63 of the proα1(I) C-propeptide) reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text. Central biochemical characterization of both chains. - id: PMID:14738308 title: Phylogenetic analysis of vertebrate fibrillar collagen locates the position of zebrafish alpha3(I) and suggests an evolutionary link between collagen alpha chains and hox clusters. findings: - statement: alpha3(I) is phylogenetically closest to alpha1(I) and likely arose from its duplication in the actinopterygian genome duplication. supporting_text: support the hypothesis that the alpha3(I) chain arose from a duplication of the alpha1(I) gene reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract only. - id: PMID:34430038 title: Phylogenetic analyses of ray-finned fishes (Actinopterygii) using collagen type I protein sequences. findings: - statement: alpha3(I) is the fastest-evolving type I collagen chain in ray-finned fishes. supporting_text: with the α3 (I) sequence evolving the fastest, followed by the α2 (I) chain reference_review: relevance: LOW correctness: VERIFIED review_notes: Full text; comparative context for the paralog pair.