Alternative titles; symbols
HGNC Approved Gene Symbol: LAMA4
Cytogenetic location: 6q21 Genomic coordinates (GRCh38) : 6:112,107,931-112,254,985 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q21 | Cardiomyopathy, dilated, 1JJ | 615235 | Autosomal dominant | 3 |
Laminin, a multidomain glycoprotein, is the major noncollagenous constituent of basement membranes. It is composed of 3 nonidentical chains: A (LAMA1; 150320), B1 (LAMB1; 150240), and B2 (LAMC1; 150290). The 3 classical laminin chains form a cruciform structure consisting of 3 short arms, each of which is formed from different chains, and a long arm composed of all 3 chains. LAMA4 encodes a variant A chain (Richards et al., 1994).
By screening a human keratinocyte cDNA library for type VII collagen sequences, Richards et al. (1994) isolated a new laminin alpha chain variant gene, LAMA4 (formerly called LAMA3). Northern blot analysis indicated that a cDNA encoding LAMA4 hybridized to a 6.45-kb mRNA, significantly smaller than the 9.5- to 10-kb mRNA of laminin A (Haaparanta et al., 1991).
Iivanainen et al. (1995) cloned the laminin alpha-4 cDNA by screening a fetal lung library with a PCR product generated from primers based on a partial laminin-like sequence reported by GenBank. The complete cDNA is approximately 6.2 kb long and encodes a predicted protein of 1,816 amino acids. The domain structure of the protein is similar to the alpha-3 chain (LAMA3, also called BM600), both of which resemble truncated versions of alpha-1 and alpha-2 in which approximately 1,200 residues at the amino end have been lost. Northern blots showed strong expression of the mRNA in adult heart, lung, ovary, small and large intestines, liver, and placenta.
Richards et al. (1997) determined that the LAMA4 gene contains 39 exons and spans 122 kb.
Using PCR on genomic DNA, flow-sorted chromosomes, and fluorescence in situ hybridization, Richards et al. (1994) localized the LAMA4 gene to human chromosome 6q21. In this abstract, the authors referred to the gene as LAMA3; in the related article, Richards et al. (1994) used the corrected symbol, LAMA4.
Knoll et al. (2007) sequenced the LAMA4 gene in 180 Caucasian patients with severe dilated cardiomyopathy (CMD1JJ; 615235) and identified a nonsense (R1073X; 600133.0001) and a missense (P943L; 600133.0002) mutation in 2 patients, respectively. Genotyping an additional 374 Caucasian CMD patients for those mutations identified 1 more patient with the P943L mutation. Screening the LAMA4 gene by SSCP in an additional 200 Japanese CMD patients revealed no variants.
Thyboll et al. (2002) noted that LAMA4 is expressed in basement membranes such as those beneath endothelia, the perineurium of peripheral nerves, and around developing muscle fibers. Lama4-null mice presented with hemorrhages during the embryonic and neonatal period. Newborns were lethargic, pale, and yellowish (icteric). They showed extensive bleeding and deterioration of microvessel growth in experimental angiogenesis, as well as mild locomotion defects. Histologic examination of newborn mice revealed delayed deposition of type IV collagen (120130) and nidogen (131390) into capillary basement membranes. Electron microscopy showed discontinuities in the lamina densa.
Wang et al. (2006) generated Lama4 -/- mice and observed gradual development of cardiac hypertrophy and impaired cardiac function by 40 weeks of age, with histology showing multiple foci of muscle degeneration and fibrosis throughout the heart. Cardiomyocytes isolated from Lama4 -/- hearts maintained their contractility in vivo. However, elevated levels of hypoxia-inducible factor-1-alpha (HIF1A; 603348) and vascular endothelial growth factor-A (VEGFA; 192240), along with multiple foci of cardiomyocyte degeneration and fibrosis, suggested sustained cardiac ischemia. Electron microscopy confirmed malformed blood vessels and wide pericapillary extracellular matrix (ECM) spaces, suggesting the presence of microcirculation abnormalities in Lama4 -/- mutant hearts. Wang et al. (2006) concluded that mutation in the laminin alpha-4 chain leads to an abnormal cardiovascular ECM structure that causes insufficient oxygen supply to the heart.
Using Lama4 -/- mice to evaluate active and passive experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS; 126200), by immunofluorescence, confocal, and electron microscopy and flow cytometric analysis, Wu et al. (2009) observed a compensatory ubiquitous expression of Lama5 (601033) in all blood vessels, independent of responses to proinflammatory cytokines. Lama4 -/- mice showed significantly lower susceptibility to active EAE and resistance to passive EAE by transfer of encephalitogenic wildtype T cells compared with wildtype mice. Elimination of integrin alpha-6 (ITGA6; 147556)/beta-1 (ITGB1; 135630)-positive T cells through Itga6 -/- bone marrow chimeras also resulted in lower EAE severity. Wu et al. (2009) concluded that LAMA5 directly inhibits integrin alpha-6/beta-1-mediated T-cell migration through LAMA4, and that T cells use mechanisms distinct from other immune cells to penetrate the endothelial basement membrane barrier.
In a woman with severe dilated cardiomyopathy (CMD1JJ; 615235), who had been diagnosed at 29 years of age and was a candidate for heart transplantation with an ejection fraction of only 20%, Knoll et al. (2007) identified heterozygosity for a 3217C-T transition in the LAMA4 gene, resulting in an arg1073-to-ter (R1073X) substitution predicted to delete 4 of the 5 LG domains at the C terminus of the LAMA4 protein and thus impair interaction with integrin molecules. The patient's deceased father was known to have had heart failure. The mutation was not found in her unaffected son or in 362 well-characterized Caucasian controls. Cell-attachment assay demonstrated a significant decrease of endothelial cell adherence with the R1073X mutant compared to wildtype, and the mutant had significantly higher equilibrium dissociation constants to immobilized alpha-3 (605025)-beta-1 (135630) integrin than wildtype. Immunohistochemistry on a myocardial biopsy sample revealed a significant loss of endothelial cells in the patient.
In 2 unrelated men with severe dilated cardiomyopathy (CMD1JJ; 615235), who were diagnosed at 53 years and 68 years of age and had ejection fractions of 29% and 31%, respectively, Knoll et al. (2007) identified heterozygosity for a 2828C-T transition in the LAMA4 gene, resulting in a pro943-to-leu (P943L) substitution at a highly conserved residue in the loop of the LG1 domain. The mutation was not found in 362 well-characterized Caucasian controls. Cell-attachment assay demonstrated a significant decrease of endothelial cell adherence with the P943L mutant compared to wildtype, and the mutant had significantly higher equilibrium dissociation constants to immobilized alpha-3 (605025)-beta-1 (135630) integrin than wildtype. Immunohistochemistry on a myocardial biopsy sample revealed a significant loss of endothelial cells in both patients.
Haaparanta, T., Uitto, J., Ruoslahti, E., Engvall, E. Molecular cloning of the cDNA encoding human laminin A chain. Matrix 11: 151-160, 1991. [PubMed: 1714537] [Full Text: https://doi.org/10.1016/s0934-8832(11)80153-8]
Iivanainen, A., Sainio, K., Sariola, H., Tryggvason, K. Primary structure and expression of a novel human laminin alpha-4 chain. FEBS Lett. 365: 183-188, 1995. [PubMed: 7781776] [Full Text: https://doi.org/10.1016/0014-5793(95)00462-i]
Knoll, R., Postel, R., Wang, J., Kratzner, R., Hennecke, G., Vacaru, A. M., Vakeel, P., Schubert, C., Murthy, K., Rana, B. K., Kube, D., Knoll, G., and 17 others. Laminin-alpha-4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells. Circulation 116: 515-525, 2007. [PubMed: 17646580] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.107.689984]
Richards, A., Luccarini, C., Pope, F. M. The structural organisation of LAMA4, the gene encoding laminin alpha4. Europ. J. Biochem. 248: 15-23, 1997. [PubMed: 9310354] [Full Text: https://doi.org/10.1111/j.1432-1033.1997.t01-1-00015.x]
Richards, A. J., Al-Imara, L., Carter, N. P., Lloyd, J. C., Leversha, M. A., Pope, F. M. Localization of the gene (LAMA4) to chromosome 6q21 and isolation of a partial cDNA encoding a variant laminin A chain. Genomics 22: 237-239, 1994. [PubMed: 7959779] [Full Text: https://doi.org/10.1006/geno.1994.1372]
Richards, A. J., Al-Imara, L., Carter, N. P., Lloyd, J. C., Pope, F. M. A laminin A variant gene (LAMA3) is present on chromosome 6q21 (Abstract) J. Med. Genet. 31: 164 only, 1994.
Thyboll, J, Kortesmaa, J., Cao, R, Soininen, R., Wang, L., Iivanainen, A., Sorokin, L., Risling, M., Cao, Y., Tryggvason, K. Deletion of the laminin alpha4 chain leads to impaired microvessel maturation. Molec. Cell. Biol. 22: 1194-1202, 2002. [PubMed: 11809810] [Full Text: https://doi.org/10.1128/MCB.22.4.1194-1202.2002]
Wang, J., Hoshijima, M., Lam, J., Zhou, Z., Jokiel, A., Dalton, N. D., Hultenby, K., Ruiz-Lozano, P., Ross, J., Jr., Tryggvason, K., Chien, K. R. Cardiomyopathy associated with microcirculation dysfunction in laminin alpha-4 chain-deficient mice. J. Biol. Chem. 281: 213-220, 2006. [PubMed: 16204254] [Full Text: https://doi.org/10.1074/jbc.M505061200]
Wu, C., Ivars, F., Anderson, P., Hallmann, R., Vestweber, D., Nilsson, P., Robenek, H., Tryggvason, K., Song, J., Korpos, E., Loser, K., Beissert, S., Georges-Labouesse, E., Sorokin, L. M. Endothelial basement membrane laminin alpha-5 selectively inhibits T lymphocyte extravasation into the brain. Nature Med. 15: 519-527, 2009. [PubMed: 19396173] [Full Text: https://doi.org/10.1038/nm.1957]