HGNC Approved Gene Symbol: COL13A1
Cytogenetic location: 10q22.1 Genomic coordinates (GRCh38): 10:69,801,906-69,959,144 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.1 | Myasthenic syndrome, congenital, 19 | 616720 | Autosomal recessive | 3 |
The COL13A1 gene encodes a nonfibrillar transmembrane collagen that plays an autocrine role in the development and maturation of the neuromuscular junction (summary by Latvanlehto et al., 2010).
Tikka et al. (1988) isolated and partially characterized the gene for the alpha-1 chain of type XIII collagen. Some of the features resembled those of genes for fibrillar collagens, but other features were distinctly different. Analysis of overlapping cDNA clones and nuclease S1 mapping of mRNAs indicated 1 alternative splicing site causing a deletion of 36 bp from the mature mRNA. The 36 bp represented a single exon. Furthermore, a 45-bp exon was also subject to alternative splicing. Of the 3 major groups of collagens--the fibrillar collagens, the large nonfibrillar collagens, and the short-chain collagens--type XIII collagen belongs to the third group.
In mouse skeletal muscle, Latvanlehto et al. (2010) showed that Col13a1 was expressed in muscle fiber and concentrated at the postsynaptic membrane at the neuromuscular junction. The protein was both embedded in the plasma membrane (110-kD form) and shed into the synaptic cleft (110-kD form). Developmentally, the gene was expressed after synapses formed and matured, and persisted there throughout life.
Logan et al. (2015) demonstrated that COL13A1 localizes to the motor endplate in normal human muscle. Western blot analysis indicated that the COL13A1 endogenous muscle protein was produced from transcript variant 21, which is smaller than the COLA13A1 isoform 1 present in HEK293 cells. Transcript variant 21 has exons 3, 5, 6, and 30 spliced out.
Shows et al. (1989) mapped the COL13A1 gene to 10q22 by a combination of somatic cell hybrid study and in situ hybridization. Pajunen et al. (1989) assigned the COL13A1 gene to 10q11-qter by Southern blot hybridization of DNA from human/rodent somatic cell hybrids.
The gene for type XIII collagen (COL13A1) and that for the alpha-1 subunit of prolyl 4-hydroxylase (P4HA1; 176710) had been assigned to 10q22 and 10q21.3-q23.1 by isotopic in situ hybridization. Horelli-Kuitunen et al. (1997) applied fluorescence in situ hybridization (FISH) combined with targets representing different levels of resolution to determine the order of these genes along chromosome 10, their transcriptional orientation, and the distance between them. Using mechanically stretched chromosomes they determined the order to be cen-COL13A1-P4HA1-tel. By combining the data from stretched chromosomes and interphase nuclei, they found that the transcriptional orientation was tail-to-tail. The distance between the genes was measured by fiber FISH to be approximately 550 kb.
In cultured mouse myotubes, Latvanlehto et al. (2010) found that soluble Col13a1 enhanced the maturation of acetylcholine receptors (AChR) at the postsynaptic region in the neuromuscular junction. The findings were consistent with an autocrine signaling role for shed Col13a1 at the neuromuscular junction.
In 3 patients from 2 unrelated families with congenital myasthenic syndrome-19 (CMS19; 616720), Logan et al. (2015) identified 2 different homozygous truncating mutations in the COL13A1 gene (120350.0001 and 120350.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Patient muscle showed absence of COL13A1 at the motor endplate, consistent with a complete loss of function. Expression of the mutation in mouse muscle cells resulted in a significant decrease in acetylcholine receptor (AChR) clustering at the postsynaptic membrane during myotube differentiation.
In 6 patients from 3 unrelated consanguineous families with CMS19, Dusl et al. (2019) identified homozygous mutations in the COL13A1 gene (120350.0003-120350.0005). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the families. Functional studies were not performed.
Rodriguez Cruz et al. (2019) identified biallelic mutations in the COL13A1 gene in 16 patients from 11 families with CMS19. (Family 11 appeared to be the same as family B reported by Dusl et al. (2019).) The mutations, which were identified by whole-exome sequencing and confirmed with Sanger sequencing, segregated with disease in the families. The mutations included 4 nonsense, 3 frameshift, 3 splice site, and 3 missense. Functional studies were not performed.
Sund et al. (2001) developed transgenic mice that expressed truncated Col13a1 as well as the normal protein. Shortened Col13a1 chains were expressed by fibroblasts. Transgenic expression led to 2 distinct phenotypes of fetal lethality in offspring from heterozygous mating. Early phenotype fetuses were aborted by day 10.5 of development due to a lack of fusion of the chorionic and allantoic membranes. Late phenotype fetuses were aborted by day 13.5 and displayed weak heartbeat, defects of the adherence junctions in the heart with detachment of myofilaments, and abnormal staining for the adherence junction component cadherin (see 192090). Decreased microvessel formation was observed in certain regions of the fetus and placenta. Sund et al. (2001) concluded that COL13A1 has a role in adhesive interactions that are necessary for normal development.
Kvist et al. (2001) found that transgenic mice with an altered Col13a1 gene lacking the short cytosolic and transmembrane domains were not phenotypically different from their normal littermates. However, skeletal muscle biopsy showed some abnormalities, including smaller muscle fibers, focal regions of abnormal myofibers with fuzzy plasma and basement membranes along the muscle fiber and at the myotendinous junctions, disorganized myofilaments, and streaming Z-discs. Immunohistochemical studies showed that the mutant protein was not located properly at the plasma membrane of skeletal muscle, but was located in the adjacent extracellular matrix. These histologic abnormalities were more pronounced in older mice, suggesting a progressive condition, and exercise induced more significant muscle fiber degeneration and inflammation in mutant mice compared to controls. Cultured fibroblasts from the mutant mice showed decreased adhesion to collagen type IV.
Latvanlehto et al. (2010) found the Col13a1-null mice grew more slowly compared to wildtype mice and showed tremors and generally worse general condition with age. Skeletal muscle fibers showed abnormal AChR cluster at the postsynaptic region of the neuromuscular junction; abnormal Schwann cells enwrapped nerve terminals and invaginated into the synaptic cleft, resulting in a decreased contact surface for neurotransmission. Many postsynaptic membranes were not apposed by nerved terminals. Some presynaptic defects were also noted, including degenerative changes at the active zone and failure of synaptic vesicles to properly cluster at nerve terminals. Electrophysiologic studies showed decreased amplitude of postsynaptic potentials, diminished probabilities of spontaneous release, and reduction in the readily releasable neurotransmitter pool. There was a slight decrement in the response to repetitive stimulation.
In a 2-year-old girl, born of unrelated parents of white European origin, with congenital myasthenic syndrome-19 (CMS19; 616720), Logan et al. (2015) identified a homozygous 1-bp deletion (c.1171delG, NM_001130103.1) in the COL13A1 gene, resulting in a frameshift and premature termination (Leu392SerfsTer71). The mutation, which was found by whole-exome sequencing, was not present in the ExAC database or in an in-house database of 3,100 control individuals. The patient's unaffected mother was heterozygous for the mutation; DNA from the father was not available. Patient muscle showed absence of COL13A1 at the motor endplate, consistent with a complete loss of function. Expression of the mutation in mouse muscle cells resulted in a significant decrease in acetylcholine receptor (AChR) clustering at the postsynaptic membrane during myotube differentiation.
In 2 sibs, born of consanguineous parents of Indian descent, with congenital myasthenic syndrome-19 (CMS19; 616720), Logan et al. (2015) identified a homozygous 1-bp deletion (c.523-1delG, NM_001130103.1), resulting in a splice site mutation and predicted to result in premature termination (Gly175ValfsTer20). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the ExAC database or in an in-house database of 3,100 control individuals. Functional studies of the variant were not performed.
In 2 Portuguese sibs, born to consanguineous parents, with congenital myasthenic syndrome-19 (CMS19; 616720), Dusl et al. (2019) identified homozygosity for a 3-bp deletion and 4-bp insertion (c.1884_1886delinsCCCT) in the COL13A1 gene, predicted to result in a frameshift at residue thr629 in the COLI-3 collagenous domain. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the family. The variant was not present in the gnomAD, EVS, and dbSNP databases. Functional studies were not performed.
In 2 Spanish sibs (family B), born to consanguineous parents, with congenital myasthenic syndrome-19 (CMS19; 616720), Dusl et al. (2019) identified homozygosity for a c.648C-G transition in the COL13A1 gene, resulting in a tyr216-to-ter (Y216X) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the family. The variant was not present in the gnomAD, EVS, and dbSNP databases. Functional studies were not performed.
In 2 German sibs, born to consanguineous parents, with congenital myasthenic syndrome-19 (CMS19; 616720), Dusl et al. (2019) identified homozygosity for a 1-bp deletion (c.1619delA) in the COL13A1 gene, predicted to result in a frameshift at residue glu543 in the COLI-3 collagenous domain. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the family. The variant was not present in the gnomAD, EVS, and dbSNP databases. Functional studies were not performed.
Dusl, M., Moreno, T., Munell, F., Macaya, A., Gratacos, M., Abicht, A., Strom, T. M., Lochmuller, H., Senderek, J. Congenital myasthenic syndrome caused by novel COL13A1 mutations. J. Neurol. 266: 1107-1112, 2019. [PubMed: 30767057] [Full Text: https://doi.org/10.1007/s00415-019-09239-7]
Horelli-Kuitunen, N., Kvist, A.-P., Helaakoski, T., Kivirikko, K., Pihlajaniemi, T., Palotie, A. The order and transcriptional orientation of the human COL13A1 and P4HA genes on chromosome 10 long arm determined by high-resolution FISH. Genomics 46: 299-302, 1997. [PubMed: 9417920] [Full Text: https://doi.org/10.1006/geno.1997.5015]
Kvist, A.-P., Latvanlehto, A., Sund, M., Eklund, L., Vaisanen, T., Hagg, P., Sormunen, R., Komulainen, J., Fassler, R., Pihlajaniemi, T. Lack of cytosolic and transmembrane domains of type XIII collagen results in progressive myopathy. Am. J. Path. 159: 1581-1592, 2001. [PubMed: 11583983] [Full Text: https://doi.org/10.1016/S0002-9440(10)62542-4]
Latvanlehto, A., Fox, M. A., Sormunen, R., Tu, H., Oikarainen, T., Koski, A., Naumenko, N., Shakirzyanova, A., Kallio, M., Ilves, M., Giniatullin, R., Sanes, J. R., Pihlajaniemi, T. Muscle-derived collagen XIII regulates maturation of the skeletal neuromuscular junction. J. Neurosci. 30: 12230-12241, 2010. [PubMed: 20844119] [Full Text: https://doi.org/10.1523/JNEUROSCI.5518-09.2010]
Logan, C. V., Cossins, J., Rodriguez Cruz, P. M., Parry, D. A., Maxwell, S., Martinez-Martinez, P., Riepsaame, J., Abdelhamed, Z. A., Lake, A. V. R., Moran, M., Robb, S., Chow, G., Sewry, C., Hopkins, P. M., Sheridan, E., Jayawant, S., Palace, J., Johnson, C. A., Beeson, D. Congenital myasthenic syndrome type 19 is caused by mutations in COL13A1, encoding the atypical non-fibrillar collagen type XIII alpha-1 chain. Am. J. Hum. Genet. 97: 878-885, 2015. [PubMed: 26626625] [Full Text: https://doi.org/10.1016/j.ajhg.2015.10.017]
Pajunen, L., Tamminen, M., Solomon, E., Pihlajaniemi, T. Assignment of the gene coding for the alpha 1 chain of collagen type XIII (COL13A1) to human chromosome region 10q11-qter. Cytogenet. Cell Genet. 52: 190-193, 1989. [PubMed: 2630191] [Full Text: https://doi.org/10.1159/000132875]
Rodriguez Cruz, P. M., Cossins, J., Etephan E. de P., Munell, F., Selby, K., Hirano, M., Maroofin, R., Yahya, M., Mehrjardi, V., Chow, G., Carr, A., Manzur, A., and 21 others. The clinical spectrum of the congenital myasthenic syndrome resulting from COL13A1 mutations. Brain 142: 1547-1560, 2019. [PubMed: 31081514] [Full Text: https://doi.org/10.1093/brain/awz107]
Shows, T. B., Tikka, L., Byers, M. G., Eddy, R. L., Haley, L. L., Henry, W. M., Prockop, D. J., Tryggvason, K. Assignment of the human collagen alpha-1(XIII) chain gene (COL13A1) to the q22 region of chromosome 10. Genomics 5: 128-133, 1989. [PubMed: 2767682] [Full Text: https://doi.org/10.1016/0888-7543(89)90096-7]
Sund, M., Ylonen, R., Tuomisto, A., Sormunen, R., Tahkola, J., Kvist, A.-P., Kontusaari, S., Autio-Harmainen, H., Pihlajaniemi, T. Abnormal adherence junctions in the heart and reduced angiogenesis in transgenic mice overexpressing mutant type XIII collagen. EMBO J. 20: 5153-5164, 2001. [PubMed: 11566879] [Full Text: https://doi.org/10.1093/emboj/20.18.5153]
Tikka, L., Pihlajaniemi, T., Henttu, P., Prockop, D. J., Tryggvason, K. Gene structure for the alpha-1 chain of a human short-chain collagen (type XIII) with alternatively spliced transcripts and translation termination codon at the 5-prime end of the last exon. Proc. Nat. Acad. Sci. 85: 7491-7495, 1988. [PubMed: 2459707] [Full Text: https://doi.org/10.1073/pnas.85.20.7491]