Alternative titles; symbols
HGNC Approved Gene Symbol: LAMA1
SNOMEDCT: 763344007;
Cytogenetic location: 18p11.31 Genomic coordinates (GRCh38): 18:6,941,742-7,117,797 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18p11.31 | Poretti-Boltshauser syndrome | 615960 | Autosomal recessive | 3 |
Laminin is a basement membrane protein composed of 3 nonidentical chains arranged in a cross-shaped structure: the 400-kD laminin A (LAMA1), the 230-kD laminin B1 (LAMB1; 150240), and the 220-kD laminin B2 (LAMB2, or LAMC1; 150290) (Paulsson et al., 1985).
Haaparanta et al. (1991) reported the nucleotide sequence of LAMA cDNA. The ORF encodes 3,075 amino acids.
Nissinen et al. (1991) cloned human LAMA from a gestational choriocarcinoma (JAR) cell line cDNA library. The deduced full-length 3,075-amino acid LAMA protein contains a 17-amino acid N-terminal signal sequence, followed by the mature laminin A chain of 3,058 amino acids. The N-terminal half of the A chain contains 3 globular domains that alternate with 3 domains composed of cysteine-rich internal repeats. The 950-amino acid C-terminal domain is made up of 5 internal repeats and contains a protein-binding RGD motif. The laminin A chain contains 30 potential N-glycosylation sites. The mature human laminin A chain shares 76% amino acid identity with the mature 3,060-amino acid mouse chain. The RGD motif in mouse is located in an N-terminal domain rather than the C-terminal domain, as in human. Northern blot analysis of several newborn human tissues, full-term placenta, and JAR cells detected a 9.5-kb transcript that was strongly expressed in JAR cells, with much weaker expression in newborn kidney only.
Using a monoclonal antibody specific for laminin A1 for immunohistochemical analysis of adult human tissues, Virtanen et al. (2000) found that laminin A1 expression was restricted to epithelial basement membranes (BMs) in select tissues, including seminiferous tubules, kidney, thyroid, salivary and mammary glands, and cervix. Laminin A was also detected in stroma of endometrium. Immunohistochemical analysis of fetal human tissues revealed developmentally regulated laminin A1 expression in epithelial BMs that differed from the adult pattern. Laminin A1 expression was confined to capillary walls in fetal cerebrum and cerebellum and in adult cerebrum and spinal cord. In cultured renal proximal tubule epithelia (RPTE) cells, laminin A1 chain localized in a fibrillar network on the cell surface. Western blot analysis of JAR and human RPTE cells detected laminin A1 at an apparent molecular mass of 400 kD.
By immunohistochemical analysis of mouse tissues, Edwards et al. (2010) found Lama1 expression in basal lamina of renal cortical tubules, testis seminiferous epithelium, and in retina.
Virtanen et al. (2000) found that human JAR cells bound to human or mouse laminin A1 and that this binding required integrin beta-1 (ITGB1; 135630).
Mattei et al. (1989) used in situ hybridization to localize the human laminin A locus to chromosome 18p11.31. (See Nagayoshi et al., 1989.) By study of mouse-Chinese hamster somatic cell hybrids, Kaye et al. (1990) assigned the gene for laminin A to mouse chromosome 17 and confirmed the assignment of the gene for laminin B2 to mouse chromosome 1.
In 7 patients from 5 unrelated families with Poretti-Boltshauser syndrome (PTBHS; 615960), Aldinger et al. (2014) identified homozygous or compound heterozygous mutations in the LAMA1 gene (see, e.g., 150320.0001-150320.0005). All of the mutations resulted in premature termination or a splicing defect, consistent with a loss of function. The mutations were found by whole-exome sequencing. Functional studies of the variants or studies on patient cells were not performed. The phenotype was characterized by cerebellar dysplasia, cerebellar vermis atrophy, cerebellar cysts in most patients, high myopia, variable retinal dystrophy, and eye movement abnormalities. All patients had delayed motor development, and most had speech delay, although cognitive function was variable. Aldinger et al. (2014) noted that mutations in other laminin-encoding genes result in a spectrum of brain malformations (see, e.g., LAMB1, 150240 and LAMC3, 604349).
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, and LAMC1.
Laminin-2 chain (LAMA2; 156225) deficiency in humans and mice leads to severe forms of congenital muscular dystrophy (607855). Gawlik et al. (2004) generated mice expressing a Lama1 transgene in skeletal muscle of Lama2-deficient mice. Lama1 is not normally expressed in muscle, but transgenic Lama1 was incorporated into muscle basement membranes, and normalized the compensatory changes of expression of certain other laminin chains (LAMA4, 600133; LAMB2, 150325). In 4-month-old mice, Lama1 could fully prevent the development of muscular dystrophy in several muscles, and partially in others. Gawlik et al. (2004) concluded that the Lama1 transgene not only reversed the appearance of histopathologic features of the disease to a remarkable degree, but also greatly improved health and longevity of the mice.
Edwards et al. (2010) reported a chemically induced mouse mutation, Nmf223, that resulted in retinal vasculopathy characterized by vitreal fibroplasia and vessel tortuosity. Nmf223 homozygotes had reduced electroretinogram responses, particularly following dark adaptation, that correlated with thinning of the retinal inner nuclear layer, abnormal migration of retinal astrocytes into the vitreous, and persistence of hyaloid vasculature. Loss of normal retinal structure and electroretinal responses progressed slowly and stopped after 1 year of age. Edwards et al. (2010) identified the nmf223 mutation as a tyr265-to-cys (Y265C) substitution within the conserved YYY motif near the N terminus of Lama1. Using a bacterial 2-hybrid assay, they showed that the mutation perturbed interaction of mutant Lama1 with wildtype Lama1, Lamab1, and Lamac1. To avoid early embryonic lethality, Edwards et al. (2010) conditionally deleted Lama1 in mice in the epiblast stage. Lama1 -/- mice were slightly smaller than wildtype at birth, but recovered by 8 weeks of age. Both male and female Lama1 -/- mice had normal life spans and were fertile. Retinal defects in Lama1 -/- mice were more severe than those observed in homozygous nmf223 mice, with complete absence of the inner limiting membrane and behavioral blindness at 1 year of age.
Heng et al. (2011) found that conditional knockout (cko) of the Lama1 gene in embryonic mouse cells reduced the size of the cerebellum and caused abnormal lobule organization and fissures. Hemispheres were strongly atrophied. Lama1 cko mice showed partial disruption of the meningial basement membrane, although basement membrane around cerebellar vessels appeared normal. Lama1 cko cerebellum showed excessive proliferation of granule cell precursors in the external granular layer, but also massive apoptosis between postnatal day 7 (P7) and P20, resulting in net reduction in cell number. Absence of Lama1 also disorganized the Bergmann glia scaffold, which likely caused the misplacement of granule cells and aberrant folia formation.
Ichikawa-Tomikawa et al. (2012) confirmed that Lama1 -/- mice died by embryonic day 7 due to absence of the Reichert membrane (Miner et al., 2004). Conditional Lama1 knockout in epiblasts resulted in mice that completed gestation and survived postnatally with normal sexual development and fertility. However, Lama1 cko mice displayed abnormal behavior in tail suspension and rotarod tests, and showed reduced stride length and abnormal locomotion pattern. Similar to the findings of Heng et al. (2011), Ichikawa-Tomikawa et al. (2012) reported that Lama1 cko mice exhibited impaired formation of cerebellum, with defects in conformation of the meninges, decreased proliferation and migration of granule cell precursors, disorganized Bergmann glial fibers and endfeet, and defects in arrangement and number of dendritic processes in Purkinje cells.
In a 3-year-old Iranian girl, born of consanguineous parents, with Poretti-Boltshauser syndrome (PTBHS; 615960), Aldinger et al. (2014) identified a homozygous T-to-G transversion in the donor site for exon 5 of the LAMA1 gene (c.588+2T-G), resulting in a splice site mutation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases, or in 2,000 in-house exome samples.
In a girl with Poretti-Boltshauser syndrome (PTBHS; 615960), Aldinger et al. (2014) identified compound heterozygous mutations in the LAMA1 gene: a 13-bp deletion (c.7965-15_7965-3del) that is predicted to alter splicing, and a 1-bp deletion (c.2986delA; 150320.0003), resulting in a frameshift and premature termination (Thr996HisfsTer28). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. They were not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases, or in 2,000 in-house exome samples.
For discussion of the 1-bp deletion in the LAMA1 gene (c.2986delA) that was found in compound heterozygous state in a patient with Poretti-Boltshauser syndrome (PTBHS; 615960) by Aldinger et al. (2014), see 150320.0002.
In 2 sisters with Poretti-Boltshauser syndrome (PTBHS; 615960), Aldinger et al. (2014) identified compound heterozygous mutations in the LAMA1 gene: a 2-bp deletion (c.2816_2817delAT), resulting in a frameshift and premature termination (Tyr939LeufsTer27) and a c.555T-G transversion, resulting in a tyr185-to-ter (Y185X; 150320.0005) substitution.
For discussion of the tyr185-to-ter (Y185X) mutation in the LAMA1 gene that was found in compound heterozygous state in patients with Poretti-Boltshauser syndrome (PTBHS; 615960) by Aldinger et al. (2014), see 150320.0004.
Aldinger, K. A., Mosca, S. J., Tetreault, M., Dempsey, J. C., Ishak, G. E., Hartley, T., Phelps, I. G., Lamont, R. E., O'Day, D. R., Basel, D., Gripp, K. W., Baker, L., and 9 others. Mutations in LAMA1 cause cerebellar dysplasia and cysts with and without retinal dystrophy. Am. J. Hum. Genet. 95: 227-234, 2014. Note: Erratum: Am. J. Hum. Genet. 95: 472 only, 2014. [PubMed: 25105227] [Full Text: https://doi.org/10.1016/j.ajhg.2014.07.007]
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]
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Gawlik, K., Miyagoe-Suzuki, Y., Ekblom, P., Takeda, S., Durbeej, M. Laminin alpha-1 chain reduces muscular dystrophy in laminin alpha-2 chain deficient mice. Hum. Molec. Genet. 13: 1775-1784, 2004. [PubMed: 15213105] [Full Text: https://doi.org/10.1093/hmg/ddh190]
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Ichikawa-Tomikawa, N., Ogawa, J., Douet, V., Xu, Z., Kamikubo, Y., Sakurai, T., Kohsaka, S., Chiba, H., Hattori, N., Yamada, Y., Arikawa-Hirasawa, E. Laminin alpha-1 is essential for mouse cerebellar development. Matrix Biol. 31: 17-28, 2012. [PubMed: 21983115] [Full Text: https://doi.org/10.1016/j.matbio.2011.09.002]
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Miner, J. H., Li, C., Mudd, J. L., Go, G., Sutherland, A. E. Compositional and structural requirements for laminin and basement membranes during mouse embryo implantation and gastrulation. Development 131: 2247-2256, 2004. [PubMed: 15102706] [Full Text: https://doi.org/10.1242/dev.01112]
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Virtanen, I., Gullberg, D., Rissanen, J., Kivilaakso, E., Kiviluoto, T., Laitinen, L. A., Lehto, V.-P., Ekblom, P. Laminin alpha-1-chain shows a restricted distribution in epithelial basement membranes of fetal and adult human tissues. Exp. Cell Res. 257: 298-309, 2000. [PubMed: 10837144] [Full Text: https://doi.org/10.1006/excr.2000.4883]