HGNC Approved Gene Symbol: COL12A1
Cytogenetic location: 6q13-q14.1 Genomic coordinates (GRCh38): 6:75,084,326-75,206,053 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q13-q14.1 | ?Ullrich congenital muscular dystrophy 2 | 616470 | Autosomal recessive | 3 |
| Bethlem myopathy 2 | 616471 | Autosomal dominant | 3 |
By screening a cDNA library constructed from tendon fibroblast mRNA for the presence of collagenous coding sequences, Gordon et al. (1987) found a clone that encodes a polypeptide that is distinct but homologous to type IX short-chain collagen polypeptides (see 120210). They named the type IX-like collagen chain alpha-1(XII) (COL12A1). Gordon et al. (1987) concluded that types IX and XII collagen are 2 homologous members of a family of unique collagenous proteins that show tissue-specific patterns of expression. Based on their structure and the properties of their genes, this family of collagen appears to be distinct from fibrillar collagens. This family, which also includes collagen types VI (see 120220) and XIV (COL14A1; 120324), is referred to as the FACIT (fibril-associated collagens with interrupted triple helices) group. Members of this group show alternating triple-helical and non-triple-helical domains.
By screening a human genomic library with a chicken Col12a1 cDNA as probe, Oh et al. (1992) isolated a partial COL12A1 cDNA. The predicted amino acid sequence showed 91% identity with mouse Col12a1.
Gerecke et al. (1997) isolated overlapping cDNA clones encoding full-length human COL12A1 polypeptides; a long variant encodes a predicted 3,063-amino acid protein and a short variant encodes a 1,899-amino acid protein. The proteins are predicted to have a 24-amino acid signal peptide, fibronectin type III repeats, von Willebrand factor A domains, and 2 triple-helical domains. Human COL12A1 shares 92% and 78% sequence identity with the mouse and chicken Col12a1 proteins, respectively. RT-PCR analysis detected both COL12A1 variants in human amnion, chorion, skeletal muscle, and small intestine, and in cell cultures of human dermal fibroblasts, keratinocytes, and endothelial cells. Only the short variant was detected in human lung, placenta, kidney, and in a squamous cell carcinoma cell line.
By Western blot and immunofluorescence analyses, Izu et al. (2021) showed that Col12a1 was expressed throughout tendon development and maturation in wildtype mice and localized in the extracellular matrix of flexor digitorum longus (FDL) tendons. Immunolocalization revealed that Col12a1 was localized on the tenocyte cell surface of FDLs from wildtype mice.
Gordon et al. (1987) found that the exon/intron structure of the gene appeared to be homologous to those of the COL9A1 (120210) and COL9A2 (120260) genes.
By linkage analysis using DNA from interspecific backcrosses with Mus spretus, Oh et al. (1992) demonstrated that the mouse Col12a1 gene is located on chromosome 9. By blot hybridization to DNA from human/hamster hybrid cell lines, Oh et al. (1992) mapped the COL12A1 gene to chromosome 6.
By fluorescence in situ hybridization, Gerecke et al. (1997) mapped the COL12A1 gene to 6q12-q13.
Izu et al. (2021) analyzed FDLs from Col12a1 -/- mice and observed that loss of Col12a1 altered both lateral tenocyte network formation and longitudinal columnar arrangement, as well as impaired tenocyte process formation and fiber organization, leading to dysfunctional fiber assembly and increased tendon stiffness. Pericellular Col12a1 was shown to provide a physical connection between neighboring tenocytes, thereby stabilizing cell shape and regulating cell-cell connection and communication. Analysis of cultured primary tenocytes from FDLs revealed decreased fibrillar collagen I (120150) in Col12a1-deficient cells, suggesting that pericellular Col12a1 regulates collagen I synthesis.
Ullrich Congenital Muscular Dystrophy 2
By mutation analysis on dermal fibroblast-derived cDNA from 2 brothers with Ullrich congenital muscular dystrophy-2 (UCMD2; 616470), Zou et al. (2014) identified homozygosity for a splice site mutation in the COL12A1 gene (120320.0001). The parents were carriers of the mutation, which was not present in the dbSNP or 1000 Genomes Project databases. Patient muscle and cultured fibroblasts showed absent extracellular immunostaining for type XII collagen. Extracellular immunostaining for type VI collagen (see 120220) and laminin-gamma-1 (LAMC1; 150290) was preserved.
Bethlem Myopathy 2
In a boy with Bethlem myopathy (BTHLM2; 616471) in whom collagen VI was found to be normal, Zou et al. (2014) screened for mutations in the COL12A1 gene and identified a de novo heterozygous missense mutation (I2334T; 120320.0002). Patient muscle and cultured fibroblasts showed decreased extracellular immunostaining for type XII collagen. Extracellular immunostaining for type VI collagen and laminin-gamma-1 (LAMC1; 150290) was preserved.
In affected members of 2 families with Bethlem myopathy who did not have mutations in the collagen VI genes (COL6A1, 120220; COL6A2, 120240, and COL6A3, 120250) identified in patients with BTHLM1 (158810) or in candidate genes related to collagen VI processing, Hicks et al. (2014) identified heterozygous mutations in the COL12A1 gene (G2786D, 120320.0003; R1965C, 120320.0004). Abnormality at the protein level was confirmed in both families by the intracellular retention of collagen XII in patient dermal fibroblasts.
In an 8-year-old Polish girl with BTHLM2, Punetha et al. (2017) identified heterozygosity for a missense mutation in the COL12A1 gene (G2777R; 120320.0005). Patient fibroblasts showed a reduced amount of formed collagen XII extracellular matrix, and there was evidence for cellular retention, consistent with a dominant-negative mode of action of the mutation, which results in the formation of abnormal COL12A1 homotrimers. The authors noted that the disorder involved both muscle and connective tissue defects.
Using trio exome sequencing and a copy number analysis tool, Coppens et al. (2022) identified a de novo heterozygous deletion of exons 45 to 54 in the COL12A1 gene (120320.0006) in a 13-year-old boy with BTHLM2. The deletion was not found in the gnomAD database.
Izu et al. (2011) generated Col12a1-null mice by targeted deletion of exons 2-5. The knockout mice had fragile bones with a disorganized collagen fiber arrangement, decreased expression of bone matrix proteins, and decreased bone-forming activity associated with delayed terminal differentiation. Zou et al. (2014) showed that the knockout mice had decreased grip strength, a delay in fiber-type transition, and a deficiency in passive force generation, while the muscle seemed more resistant to eccentric contraction-induced force drop, indicating a role for a matrix-based passive force-transducing elastic element in the generation of the weakness.
In 2 brothers, born of consanguineous Turkish parents, with Ullrich congenital muscular dystrophy-2 (UCMD2; 616470), Zou et al. (2014) identified homozygosity for a splice site donor mutation (c.8006+1G-A, NM_004370) in intron 50 of the COL12A1 gene. The mutation was predicted to result in out-of-frame skipping of exon 50, with the generation of a premature stop codon in exon 51 and loss of the 2 triple-helical domains. Skin fibroblasts and muscle from the affected individuals were devoid of immunoreactivity to type XII collagen antibodies. The parents were heterozygous for the mutation and reported a history of delayed gross motor development, with achievement of ambulation after the age of 2 years.
In a 3-year-old boy with a history of congenital hypotonia, proximal joint contractures, and distal joint hypermobility (BTHLM2; 616471), Zou et al. (2014) identified a heterozygous c.7167T-C transition (c.7167T-C, NM_004370) in the COL12A1 gene, resulting in an ile2334-to-thr (I2334T) substitution. Patient skin fibroblasts and muscle revealed markedly decreased type XII collagen immunoreactivity in the extracellular matrix and moderately decreased staining of fibroblasts intracellularly.
By whole-exome sequencing in affected members of a family with Bethlem myopathy-2 (BTHLM2; 616471), Hicks et al. (2014) identified a heterozygous c.8357G-A transition (c.8357G-A, NM_004370) in the COL12A1 gene, resulting in a gly2786-to-asp (G2786D) substitution in the triple-helical domain. Abnormality at the protein level was confirmed by the intracellular retention of collagen XII in patient dermal fibroblasts. The variant was not found in the Exome Variant Server or the 1000 Genomes Project databases.
By whole-exome sequencing in a family with Bethlem myopathy-2 (BTHLM2; 616471), Hicks et al. (2014) identified a heterozygous c.5893C-T transition (c.5893C-T, NM_004370) in the COL12A1, resulting in an arg1965-to-cys (R1965C) substitution, which introduced an unpaired cysteine residue. Abnormality at the protein level was confirmed by the intracellular retention of collagen XII in patient dermal fibroblasts. The mutation led to upregulation of genes associated with the unfolded protein response (UPR) pathway and swollen, dysmorphic, rough endoplasmic reticulum. The variant was found at a low frequency (0.016%) in African Americans, but not in European Americans, in the Exome Sequencing Project database.
In an 8-year-old Polish girl with congenital myopathy and joint laxity (BTHLM2; 616471), Punetha et al. (2017) identified heterozygosity for a c.8329G-C transversion (c.8329G-C, NM_004370.5) in the COL12A1 gene, resulting in a gly2777-to-arg (G2777R) substitution within the collagen triple helix domain. Sanger sequencing confirmed the mutation, which was not found in her mother; DNA from her father was unavailable. The variant was not found in the NHLBI Exome Variant Server or ExAC databases. Patient fibroblasts showed a reduced amount of formed collagen XII extracellular matrix. Staining in the presence of triton revealed intracellular retention of collagen XII, consistent with a dominant-negative mode of action of the mutation, which results in the formation of abnormal COL12A1 homotrimers.
In a 13-year-old boy with congenital myopathy and joint laxity (BTHLM2; 616471), Coppens et al. (2022) identified heterozygosity for a de novo heterozygous in-frame deletion of exons 45 to 54 (NM_004370.6) in the COL12A1 gene, predicted to remove the last half of the fourth vWA domain, the entire laminin-G domain, and the proximal part of the COL2 domain. The deletion, which affects both the short and long COL12A1 isoforms, was not found in gnomAD. Patient fibroblasts showed nearly complete absence of collagen XII in the extracellular matrix and increased intracellular staining.
Coppens, S., Desmyter, L., Koch, M., Ozcelik, S., O'Heir, E., Van Bogaert, P., Vilain, C., Christiaens, F. Ehlers-Danlos/myopathy overlap syndrome caused by a large de novo deletion in COL12A1. Am. J. Med. Genet. 188A: 1556-1561, 2022. [PubMed: 35019233] [Full Text: https://doi.org/10.1002/ajmg.a.62653]
Gerecke, D. R., Olson, P. F., Koch, M., Knoll, J. H. M., Taylor, R., Hudson, D. L., Champliaud, M.-F., Olsen, B. R., Burgeson, R. E. Complete primary structure of two splice variants of collagen XII, and assignment of alpha-1(XII) collagen (COL12A1), alpha-1(IX) collagen (COL9A1), and alpha-1(XIX) collagen (COL19A1) to human chromosome 6q12-q13. Genomics 41: 236-242, 1997. [PubMed: 9143499] [Full Text: https://doi.org/10.1006/geno.1997.4638]
Gordon, M. K., Gerecke, D. R., Olsen, B. R. Type XII collagen: distinct extracellular matrix component discovered by cDNA cloning. Proc. Nat. Acad. Sci. 84: 6040-6044, 1987. [PubMed: 3476925] [Full Text: https://doi.org/10.1073/pnas.84.17.6040]
Hicks, D., Farsani, G. T., Laval, S., Collins, J., Sarkozy, A., Martoni, E., Shah, A., Zou, Y., Koch, M., Bonnemann, C. G., Roberts, M., Lochmuller, H., Bushby, K., Straub, V. Mutations in the collagen XII gene define a new form of extracellular matrix-related myopathy. Hum. Molec. Genet. 23: 2353-2363, 2014. [PubMed: 24334769] [Full Text: https://doi.org/10.1093/hmg/ddt637]
Izu, Y., Adams, S. M., Connizzo, B. K., Beason, D. P., Soslowsky, L. J., Koch, M., Birk, D. E. Collagen XII mediated cellular and extracellular mechanisms regulate establishment of tendon structure and function. Matrix Biol. 95: 52-67, 2021. [PubMed: 33096204] [Full Text: https://doi.org/10.1016/j.matbio.2020.10.004]
Izu, Y., Sun, M., Zwolanek, D., Veit, G., Williams, V., Cha, B., Jepsen, K. J., Koch, M., Birk, D. E. Type XII collagen regulates osteoblast polarity and communication during bone formation. J. Cell Biol. 193: 1115-1130, 2011. [PubMed: 21670218] [Full Text: https://doi.org/10.1083/jcb.201010010]
Oh, S. P., Taylor, R. W., Gerecke, D. R., Rochelle, J. M., Seldin, M. F., Olsen, B. R. The mouse alpha-1(XII) and human alpha-1(XII)-like collagen genes are localized on mouse chromosome 9 and human chromosome 6. Genomics 14: 225-231, 1992. [PubMed: 1427837] [Full Text: https://doi.org/10.1016/s0888-7543(05)80210-1]
Punetha, J., Kesari, A., Hoffman, E. P., Gos, M., Kaminska, A., Kostera-Pruszczyk, A., Hausmanowa-Petrusewicz, I., Hu, Y., Zou, Y., Bonnemann, C. G., Jedrzejowska, M. Novel Col12A1 variant expands the clinical picture of congenital myopathies with extracellular matrix defects. Muscle Nerve 55: 277-281, 2017. [PubMed: 27348394] [Full Text: https://doi.org/10.1002/mus.25232]
Zou, Y., Zwolanek, D., Izu, Y., Gandhy, S., Schreiber, G., Brockmann, K., Devoto, M., Tian, Z., Hu, Y., Veit, G., Meier, M., Stetefeld, J., Hicks, D., Straub, V., Voermans, N. C., Birk, D. E., Barton, E. R., Koch, M., Bonnemann, C. G. Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice. Hum. Molec. Genet. 23: 2339-2352, 2014. [PubMed: 24334604] [Full Text: https://doi.org/10.1093/hmg/ddt627]