Alternative titles; symbols
HGNC Approved Gene Symbol: LAMC1
Cytogenetic location: 1q25.3 Genomic coordinates (GRCh38): 1:183,023,420-183,145,592 (from NCBI)
Laminin is a heterotrimeric extracellular matrix protein consisting of 3 chains: alpha (LAMA1; 150320), beta (LAMB1; 150240), and gamma (formerly A, B1, and B2, respectively). Several isoforms of each chain have been identified. Laminin gamma-1 is the most ubiquitously expressed laminin subunit (Burgeson et al., 1994; Miner et al., 1997).
Mattei et al. (1988) isolated a cDNA probe corresponding to a gene encoding 235 amino acids at the carboxyl end of the human laminin B2 chain. Northern blot analysis detected 2 mRNA transcripts of 8.2 kb and 5.6 kb in both normal human skin fibroblasts and 3 tumor cell lines.
Pikkarainen et al. (1988) determined the complete amino acid sequence of the laminin B2 chain by sequencing cDNA clones. Comparison with laminin B1 suggested that the 2 chains are highly homologous and are probably the products of related genes. However, based on analysis of the intron-exon structures, Kallunki et al. (1991) concluded that LAMB1 and LAMB2 had diverged considerably.
Kallunki et al. (1991) determined that the LAMC1 gene contains 28 exons. The authors concluded that the exon-intron structure of the LAMC1 gene demonstrates extensive divergence from the human laminin B1 chain gene (LAMB1; 150240), which has 34 exons. Only 3 intron locations are conserved in these 2 genes. The overall exon profile of the laminin B2 chain gene correlates only marginally with the pattern of structural domains and internal cysteine-rich repeats in the laminin B2 polypeptide chain.
Mattei et al. (1988) mapped the LAMC1 gene to chromosome 1q31 by Southern blot analysis and in situ hybridization.
Linkage Analysis
Nishimura et al. (1988) used RFLPs for family linkage studies, and by multipoint linkage analysis, placed LAMB2 between Fy (110700) and the cluster including REN (179820), DAF (125240), and CR2 (120650). The maximum lod score was 3.85 at theta = 0.23 with Fy and 4.88 at theta = 0.17 with REN.
Gedde-Dahl et al. (1994) found a suggestion of linkage between junctional epidermolysis bullosa inversa (see 226650) and a trinucleotide repeat marker in intron 20 of the LAMC1 gene. All 4 patients in 3 different families were homozygous for a particular LAMC1 allele present in only 5% of random Norwegian chromosomes. The daughter of a deceased patient in a fourth family carried the same 146-bp allele. Gedde-Dahl et al. (1994) concluded that this extreme association confirmed that the disease locus, EBR2A, is at or closely linked to LAMC1. They pointed out, however, that LAMC2 (150292), which is involved in the Herlitz type of junctional epidermolysis bullosa (226700), is sufficiently close to the LAMC1 gene that the linkage and association observed in the Norwegian families might indicate that the mutation causing the inversa type is located in the LAMC2 gene.
Associations Pending Confirmation
Nikolova et al. (2007) found a suggestion of linkage of familial pelvic organ prolapse (PVOP1; 176780) to 1q31 and identified a single-nucleotide polymorphism (SNP) in the LAMC1 promoter region for which the rare T variant segregated with the condition. The SNP, rs10911193, affected the binding site for NFIL3 (605327), a transcription factor that Nikolova et al. (2007) demonstrated to be coexpressed with LAMC1 in vaginal tissue.
See 150290.0001 for a discussion of a possible association between mutation in the LAMC1 gene and Dandy-Walker malformation with occipital cephalocele (ADDWOC; 609222).
Burgeson et al. (1994), a group of 14 leading researchers in the field of connective tissue proteins, adopted a new nomenclature for the laminins. They were numbered with arabic numerals in the order discovered. The previous A, B1, and B2 chains, and their isoforms, are alpha, beta, and gamma, respectively, followed by an arabic numeral to identify the isoform. For example, the first laminin identified from the Engelbreth-Holm-Swarm tumor (EHS) was designated laminin-1 with the chain composition alpha-1/beta-1/gamma-1. The genes for these 3 chains are LAMA1, LAMB1 (150240), and LAMC1.
In mouse, the laminin subunits alpha-1, beta-1, and gamma-1 are expressed in the preimplantation embryo before the appearance of the first basement membrane of the trophectodermal epithelium. Smyth et al. (1999) targeted the LAMC1 gene by homologous recombination in mouse embryonic stem (ES) cells. Mice heterozygous for the mutation had a normal phenotype and were fertile, whereas homozygous mutant embryos did not survive beyond day 5.5 postcoitum. These embryos lacked basement membranes, and although the blastocysts had expanded, primitive endoderm cells remained in the inner mass, and the parietal yolk sac did not develop. Cultured ES cells appeared normal after targeting both LAMC1 genes, but the embryoid bodies derived from them also lacked basement membranes, having disorganized extracellular deposits of the basement membrane proteins collagen IV (see 120130) and perlecan (142461), and the cells failed to differentiate into stable myotubes.
This variant is classified as a variant of unknown significance because its contribution to Dandy-Walker malformation with occipital cephalocele (ADDWOC; 609222) has not been confirmed.
In 3 affected members over 3 generations of an Indian family with autosomal dominant Dandy-Walker malformation with occipital cephalocele, originally reported by Ghonge et al. (2011), Darbro et al. (2013) identified heterozygosity for a c.2237C-T transition in the LAMC1 gene, resulting in a thr746-to-met (T746M) substitution at a highly conserved residue in the sixth epidermal growth factor-like domain. No functional analysis of the variant was reported.
Burgeson, R. E., Chiquet, M., Deutzmann, R., Ekblom, P., Engel, J., Kleinman, H., Martin, G. R., Meneguzzi, G., Paulsson, M., Sanes, J., Timpl, R., Tryggvason, K., Yamada, Y., Yurchenco, P. D. A new nomenclature for the laminins. Matrix Biol. 14: 209-211, 1994. [PubMed: 7921537] [Full Text: https://doi.org/10.1016/0945-053x(94)90184-8]
Darbro, B. W., Mahajan, V. B., Gakhar, L., Skeie, J. M., Campbell, E., Wu, S., Bing, X., Millen, K. J., Dobyns, W. B., Kessler, J. A., Jalali, A., Cremer, J., and 14 others. Mutations in extracellular matrix genes NID1 and LAMC1 cause autosomal dominant Dandy-Walker malformation and occipital cephaloceles. Hum. Mutat. 34: 1075-1079, 2013. [PubMed: 23674478] [Full Text: https://doi.org/10.1002/humu.22351]
Gedde-Dahl, T., Jr., Dupuy, B. M., Jonassen, R., Winberg, J.-O., Anton-Lamprecht, I., Olaisen, B. Junctional epidermolysis bullosa inversa (locus EBR2A) assigned to 1q31 by linkage and association of LAMC1. Hum. Molec. Genet. 3: 1387-1391, 1994. [PubMed: 7987320] [Full Text: https://doi.org/10.1093/hmg/3.8.1387]
Ghonge, N. P., Kanika, S. S., Poonam, B. Familial occipital cephalocele in a fetus at 21 weeks' gestation: imaging demonstration across 3 generations. (Letter) J. Ultrasound Med. 30: 1747-1751, 2011. [PubMed: 22124012] [Full Text: https://doi.org/10.7863/jum.2011.30.12.1747]
Kallunki, T., Ikonen, J., Chow, L. T., Kallunki, P., Tryggvason, K. Structure of the human laminin B2 chain gene reveals extensive divergence from the laminin B1 chain gene. J. Biol. Chem. 266: 221-228, 1991. [PubMed: 1985895]
Kallunki, T., Pikkarainen, T., Tryggvason, K., Savolainen, E.-R. A Pst I polymorphism in the human laminin B2 chain gene on 1q25-q31. Nucleic Acids Res. 17: 4423 only, 1989. [PubMed: 2787023] [Full Text: https://doi.org/10.1093/nar/17.11.4423]
Mattei, M.-G., Weil, D., Pribula-Conway, D., Bernard, M. P., Passage, E., Van Cong, N., Timpl, R., Chu, M.-L. cDNA cloning, expression and mapping of human laminin B2 gene to chromosome 1q31. Hum. Genet. 79: 235-241, 1988. [PubMed: 3402995] [Full Text: https://doi.org/10.1007/BF00366243]
Miner, J. H., Patton, B. L., Lentz, S. I., Gilbert, D. J., Jenkins, N. A., Copeland, N. G., Sanes, J. R. The laminin alpha chains: expression, developmental transitions, and chromosomal locations of alpha1-5, identification of heterodimeric laminins 8-11, and cloning of a novel alpha3 isoform. J. Cell Biol. 137: 685-701, 1997. [PubMed: 9151674] [Full Text: https://doi.org/10.1083/jcb.137.3.685]
Nikolova, G., Lee, H., Berkovitz, S., Nelson, S., Sinsheimer, J., Vilain, E., Rodriguez, L. V. Sequence variant in the laminin gamma-1 (LAMC1) gene associated with familial pelvic organ prolapse. Hum. Genet. 120: 847-856, 2007. [PubMed: 17021862] [Full Text: https://doi.org/10.1007/s00439-006-0267-1]
Nishimura, D., Buetow, K. H., Yamada, Y., Murray, J. C. RFLPs and linkage relationships of the human laminin B2 gene. Genomics 3: 393-395, 1988. [PubMed: 2907506] [Full Text: https://doi.org/10.1016/0888-7543(88)90134-6]
Pikkarainen, T., Kallunki, T., Tryggvason, K. Human laminin B2 chain: comparison of the complete amino acid sequence with the B1 chain reveals variability in sequence homology between different structural domains. J. Biol. Chem. 263: 6751-6758, 1988. [PubMed: 3360804]
Sasaki, M., Yamada, Y. The laminin B2 chain has a multidomain structure homologous to the B1 chain. J. Biol. Chem. 262: 17111-17117, 1987. [PubMed: 3680290]
Smyth, N., Vatansever, H. S., Murray, P., Meyer, M., Frie, C., Paulsson, M., Edgar, D. Absence of basement membranes after targeting the LAMC1 gene results in embryonic lethality due to failure of endoderm differentiation. J. Cell Biol. 144: 151-160, 1999. [PubMed: 9885251] [Full Text: https://doi.org/10.1083/jcb.144.1.151]