Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: LAMA2
SNOMEDCT: 111503008, 787037000;
Cytogenetic location: 6q22.33 Genomic coordinates (GRCh38) : 6:128,883,138-129,516,566 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q22.33 | Muscular dystrophy, congenital, merosin deficient or partially deficient | 607855 | Autosomal recessive | 3 |
| Muscular dystrophy, limb-girdle, autosomal recessive 23 | 618138 | Autosomal recessive | 3 |
The LAMA2 gene encodes the alpha-2 laminin subunit of the heterotrimeric extracellular protein laminin-211, also referred to as laminin-2 or merosin. The other subunits include beta-1 (LAMB1; 150240), and gamma-1, formerly called beta-2 (LAMC1; 150290). Laminin-211 binds to the glycosylated residues of alpha-dystroglycan (DAG1; 128239) in skeletal muscle fibers. Laminin-211 is also expressed in a variety of other tissues, most importantly in Schwann cells in peripheral nerves and in the brain (summary by Oliveira et al., 2018).
Merosin is a protein specifically found in the basement membranes of striated muscle and Schwann cells. It is also found in the basement membrane of placental trophoblasts. Ehrig et al. (1990) compared merosin with laminin, which is thought to be present in all basement membranes. They found that a cDNA clone derived from a merosin fragment contained a 3.4-kb open reading frame encoding 1,130 amino acids. The deduced amino acid sequence of the merosin polypeptide is similar to that of the C-terminal region of the laminin alpha-1 chain. The sequence identity between merosin and laminin is nearly 40% in this region. Like laminin, merosin is associated with the light chains laminin B1 and laminin B2, and the whole molecule has a cross-like structure similar to that of laminin. The authors estimated that the LAMA2 chain is at least 380 kD.
Vuolteenaho et al. (1994) determined the primary structure of the laminin M chain (symbolized LAMM by them) from cDNA clones isolated from human placental libraries. The complete chain contains a 22-residue signal peptide and 3,088 residues of the mature M chain (3110 residues total). The M chain has a domain structure similar to that of the human and mouse A chains. Northern blot analysis of human fetal tissues showed that the M chain was expressed in most tissues, but not in liver, thymus, or bone. In situ hybridization localized the expression of the M chain gene to cells of mesenchymal origin. In contrast, expression of the A chain was observed only in kidney, testis, neuroretina, and some regions of the brain, as determined by Northern analyses. Epithelial and endothelial cells were negative for both M and A chain gene transcripts.
Pegoraro et al. (2000) identified a novel alternatively spliced isoform of LAMA2. Direct sequencing showed that the isoform has a 138-bp in-frame deletion from nucleotides 4629 to 4766 of the coding sequence corresponding to about 70% of exon 31. This splicing event removes 46 amino acids in the cysteine-rich domain IIIa, just proximal to the triple coiled-coil region that associates with the beta-1 and gamma-1 chains of laminin. Immunofluorescent studies suggested that this isoform may impair proper laminin chain assembly.
The LAMA2 protein undergoes posttranslational processing and is cleaved at residue 2580 to yield an N-terminal 300-kD peptide and a C-terminal 80-kD peptide, which are subsequently connected through a noncovalent process (summary by Oliveira et al., 2018).
Arahata et al. (1993) indicated that merosin is the same as laminin M, a striated muscle-specific, basal-lamina-associated protein. They found that the protein was reduced in the muscle fibers in Fukuyama congenital muscular dystrophy (253800), suggesting that it may play a primary role in the pathogenesis of that disorder.
The laminin alpha-2 subunit is expressed in Schwann cells. Ng et al. (2000) provided evidence for the involvement of the specific trisaccharide unit of the phenolic glycolipid-1 (PGL1) of Mycobacterium leprae (see 246300) in determining the bacterial predilection to the peripheral nerve. PGL1 binds specifically to the native laminin-2 in the basal lamina of Schwann cell-axon units. This binding is mediated by the LG1, LG4, and LG5 modules present in the naturally cleaved fragments of the peripheral nerve LAMA2 chain, and is inhibited by the synthetic terminal trisaccharide of PGL1. PGL1 is involved in the M. leprae invasion of Schwann cells through the basal lamina in a laminin-2-dependent pathway. The results indicated a novel role of a bacterial glycolipid in determining the nerve predilection of a human pathogen.
Zhang et al. (1996) determined the genomic structure of the human LAMA2 gene. The gene spans over 260 kb and contains 64 exons. Two of the exons are unusually small, being 6 and 12 bp, respectively.
Vuolteenaho et al. (1994) localized the human LAMA2 gene to 6q22-q23 by a combination of somatic cell hybrid analysis and in situ hybridization.
By FISH, Sallinen et al. (1999) mapped the mouse Lama2 gene to chromosome 10A4-B1.
Muscular Dystrophy, Congenital Merosin-Deficient, Type 1A
In affected members of 2 families with congenital merosin-deficient muscular dystrophy type 1A (MDC1A; 607855), Helbling-Leclerc et al. (1995) identified 2 different homozygous mutations (156225.0001-156225.0002) in the LAMA2 gene. They suggested that 'the extracellular location of laminin-2 may allow new therapeutic strategies to restore its presence at the periphery of the muscle fibres and to modify the severe course of this very disabling disease.'
Complete LAMA2 deficiency causes approximately half of CMD cases. Tezak et al. (2003) noted that many loss-of-function mutations had been reported in these severe, neonatal-onset patients, but only missense mutations had been found in milder CMD with partial LAMA2 deficiency. They studied 9 patients with CMD who showed abnormal white matter signal on brain MRI and partial deficiency of LAMA2 on immunofluorescence of muscle biopsy, and identified changes in the LAMA2 sequence in 6. Except for one, each of the gene changes identified was novel, including 3 missense changes (see, e.g., 156225.0009-156225.0010) and 2 splice site mutations. The finding of partial LAMA2 deficiency by immunostaining was not specific for carriers of a LAMA2 gene mutation, as only 2 patients showed clear causative mutations, and an additional 3 showed possible mutations. The clinical presentation and the disease progression were the same in LAMA2 mutation-positive and mutation-negative CMD patients.
Di Blasi et al. (2005) identified 10 LAMA2 mutations, including 9 novel mutations, in 10 of 15 patients with congenital muscular dystrophy and undetectable or greatly reduced muscle expression of LAMA2 protein. All the mutation-positive patients had generalized hypotonia and severe weakness from birth, and all had abnormal MRI changes. One founder mutation (156225.0013) was identified and determined to originate from Albania. Two of the 5 patients without detectable LAMA2 mutations and who also did not have white matter changes were found to have mutations in the FKRP gene (606596).
Oliveira et al. (2008) identified 18 different mutations in the LAMA2 gene, including 14 novel mutations, in 50 (96%) of 52 disease alleles from 26 patients with a clinical presentation suggestive of MDC1A. Only heterozygous mutations were identified in 2 patients. Ten (31%) patients carried a common 5-kb deletion encompassing exon 56 of the LAMA2 gene (156225.0015).
Muscular Dystrophy, Limb-Girdle, Autosomal Recessive 23
In 5 patients from 4 families with autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23; 618138), Gavassini et al. (2011) identified homozygous or compound heterozygous mutations in the LAMA2 gene (see, e.g., 156225.0016 and 156225.0017). There were 4 missense mutations, 1 splice site mutation, and 1 in-frame deletion. The mutations were located in both the globular and the rod-like domains of the protein. Functional studies of the variants were not performed, but the splice site mutation was confirmed to result in a frameshift in patient cells. Muscle biopsy showed partial LAMA2 deficiency in all patients.
In a girl with LGMDR23, Chan et al. (2014) identified compound heterozygous mutations in the LAMA2 gene (Q131X, 156225.0018 and A1496V, 156225.0019). The mutations segregated with the disorder in the family. Functional studies of the variants were not performed.
In a comprehensive mutation update on LAMA2 mutations, Oliveira et al. (2018) stated that the most frequently reported genotypes are variants that create premature termination codons (PTC) in both disease alleles, are associated with complete deficiency of laminin in muscle biopsy, and cause a severe, congenital muscular dystrophy (MDC1A). In contrast, missense variants, which are present in a smaller number of cases, usually correlate with partial laminin deficiency in muscle biopsy, and cause a milder, later-onset disorder (LGMDR23).
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 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.
Dominov et al. (2005) generated mdx (300377) or Lama2-null mice that also overexpressed muscle-specific human BCL2 (151430). In mdx mice, overexpression of BCL2 failed to produce any significant differences in muscle pathology; however, in Lama2-null mice, muscle-specific overexpression of BCL2 led to a several-fold increase in life span and an increased growth rate. Dominov et al. (2005) concluded that BCL2-mediated apoptosis appeared to play a significant role in pathogenesis of congenital muscular dystrophy type 1A due to LAMA2 deficiency but not in Duchenne muscular dystrophy (DMD; 310200) due to dystrophin deficiency.
In mice, Millay et al. (2008) showed the deletion of the gene encoding cyclophilin D, Ppif (604486), rendered mitochondria largely insensitive to the calcium overload-induced swelling associated with a defective sarcolemma, thus reducing myofiber necrosis in 2 distinct models of muscular dystrophy. Mice lacking delta-sarcoglycan (Scgd-null mice; see 601411) showed markedly less dystrophic disease in both skeletal muscle and heart in the absence of Ppif. Moreover, the premature lethality associated with deletion of Lama2 was rescued, as were other indices of dystrophic disease. Treatment with the cyclophilin inhibitor Debio-025 similarly reduced mitochondrial swelling and necrotic disease manifestations in mdx mice, a model of Duchenne muscular dystrophy, and in Scgd-null mice. Thus, mitochondrial-dependent necrosis represents a prominent disease mechanism in muscular dystrophy, suggesting that inhibition of cyclophilin D could provide a new pharmacologic treatment strategy for these diseases.
In a family with merosin-deficient congenital muscular dystrophy (607855), Helbling-Leclerc et al. (1995) found a 193-bp deletion corresponding to all of exon 31 of the gene. From the sequence of flanking introns, they found an A-to-T transversion at the -2 position of the consensus acceptor splice site of exon 31. Two affected CMD children were homozygous, while their parents and sibs were heterozygous. The mutation occurred 2 nucleotides to the 5-prime side of NT4573.
In affected members of a nonconsanguineous family with congenital merosin-deficient muscular dystrophy (607855), Helbling-Leclerc et al. (1995) found by SSCP analysis aberrant conformers for exon 24 of the LAMA2 gene. Sequencing of exon 24 revealed a homozygous C-to-T substitution at position 3767 of their cDNA. The mutation caused a change in a CAA codon for glutamine to a TAA stop codon (Q1241X) in domain IVa.
In 2 sibs with mild congenital merosin-deficient muscular dystrophy (607855) in a consanguineous Saudi Arabian family, Allamand et al. (1997) found that the laminin alpha-2 chain had an internal deletion as the result of a splice site mutation in the LAMA2 gene that caused the splicing out of exon 25. The predicted protein lacked 63 amino acids in domain IVa, which forms a globular structure on the short arm of the alpha-2 chain. Antibodies against the G-domain of the laminin alpha-2 chain showed a near normal expression in skeletal muscle, whereas antibodies against the N-terminal region showed a drastic reduction. These patients appeared mildly affected compared to others who completely lacked this protein. Allamand et al. (1997) compared the situation to Becker muscular dystrophy (300376), in which in-frame deletions of the dystrophin gene (300377) result in the expression of a semifunctional protein and leads to a mild phenotype. The splice site mutation was a T-to-C transition at position +2 of the consensus donor splice site of exon 25. This mutation was found in homozygous state in both patients and induced the splicing out of exon 25 by alternately using the donor splice site of exon 24. Both parents were heterozygous.
In a patient with congenital merosin-deficient muscular dystrophy (607855) characterized by difficulty walking, hypotonia, proximal weakness, hyporeflexia, and white matter hypodensity on MRI, He et al. (2001) identified compound heterozygosity in the LAMA2 gene: a missense mutation resulting in a leu2564-to-pro (L2564P) substitution and a nonsense mutation at codon 3085 (R3085X; 156225.0005). Laminin alpha-2 antibody labeling was mildly reduced. He et al. (2001) suggested that the patient's mild phenotype correlated with partial deficiency of laminin alpha-2 due to expression of the L2564P allele. The authors noted the importance of using antibodies against different domains of the protein for correct immunohistochemical characterization.
For discussion of the arg3085-to-ter (R3085X) substitution in the LAMA2 gene that was found in compound heterozygous state in a patient with congenital merosin-deficient muscular dystrophy (607855) by He et al. (2001), see 156225.0004.
In a patient with congenital merosin-deficient muscular dystrophy (607855) characterized by motor delay with inability to walk, hypotonia, scoliosis, contractures, seizures, and white matter hypodensity on MRI, He et al. (2001) identified a homozygous 1-bp deletion (8314delA) in the LAMA2 gene, resulting in a frameshift and premature stop codon. He et al. (2001) suggested that the reduced amount of the truncated protein correlated with the severe phenotype.
In a patient with congenital merosin-deficient muscular dystrophy (607855) characterized by inability to walk, kyphoscoliosis, contractures, chest deformity, respiratory insufficiency, and white matter hypodensity on MRI, He et al. (2001) identified a 2-bp deletion (2098delAG) in the LAMA2 gene.
Coral-Vazquez et al. (2003) reported the case of an 8-month-old Mexican female, from a consanguineous family, with classic merosin-deficient congenital muscular dystrophy (607855). In addition to elevated serum creatine kinase and dystrophic changes on muscle biopsy, there were abnormalities on brain MRI. Immunofluorescence analysis demonstrated complete absence of LAMA2. In contrast, all components of the dystrophin-glycoprotein complex appeared normal. Mutation analysis of the LAMA2 gene identified a homozygous 7781C-T transition in exon 54 that resulted in an arg2578-to-ter (R2578X) mutation in the G domain of the protein. Both parents and some other relatives were carriers of the mutation.
In a patient with congenital muscular dystrophy and partial LAMA2 deficiency (607855), Tezak et al. (2003) found compound heterozygosity for a 2633T-C transition in exon 18 of the LAMA2 gene, resulting in a change of a conserved cysteine residue at codon 862 to arg (C862R), and another mutation that caused abnormalities of transcription but was not fully characterized. This patient reached the ability to walk unsupported, in contrast with patients with complete LAMA2 deficiency CMD who never achieve this ability. In her late teens, she began to lose previously acquired cognitive abilities. Although mental retardation had previously been reported in CMDs, dementia was unusual. A possible explanation is ascertainment bias, since most of the CMD patients reported were studied at a young age, while dementia may develop at a later stage of the disease.
In a patient with congenital muscular dystrophy and partial LAMA2 deficiency (607855), Tezak et al. (2003) found compound heterozygosity for a 1629G-A transition in exon 10 of the LAMA2 gene, resulting in a change of a conserved cysteine residue at codon 527 to tyr (C527Y), and a second mutation that caused transcription abnormalities but was not fully characterized.
In a patient with congenital muscular dystrophy and partial LAMA2 deficiency (607855), Pegoraro et al. (2000) identified compound heterozygosity for 2 mutations in the LAMA2 gene: a 4694C-T transition in exon 31, resulting in an arg1549-to-ter (R1549X) substitution, and a 7196C-T transition in exon 49, resulting in an arg2383-to-ter (R2383X; 156225.0012) substitution. The patient had a severe form of the disorder with central nervous system involvement including seizures, mental retardation, ventricular dilatation, and pachygyria. Each parent was heterozygous for 1 of the mutations.
For discussion of the 7196C-T transition in exon 49 of the LAMA2 gene, resulting in an arg2383-to-ter (R2383X) substitution, that was found in a patient with congenital muscular dystrophy and partial LAMA2 deficiency (607855) by Pegoraro et al. (2000), see 156225.0011.
In 2 unrelated patients with congenital merosin-deficient muscular dystrophy (MDC1A; 607855), Di Blasi et al. (2005) identified a 2901C-A transversion in exon 21 of the LAMA2 gene, resulting in a cys967-to-ter (C967X) substitution and truncation of the protein in domain IIIb. One of the patients, who was Italian, was homozygous for the C967X mutation, and the other patient, from Albania, was compound heterozygous for the C967X mutation and a 1-bp deletion (825delC) in exon 6 of the LAMA2 gene, resulting in a frameshift and premature stop codon. The C967X mutation had previously been reported in affected members of 2 Italian families originating from the southern Adriatic coast (Guicheney et al., 1998). Haplotype analysis suggested a remote founder effect, with the mutation most likely originating in Albania.
For discussion of the 1-bp deletion (825delC) in exon 6 of the LAMA2 gene, resulting in a frameshift and premature stop codon, that was found in compound heterozygous state in 2 unrelated patients with congenital merosin-deficient muscular dystrophy by Di Blasi et al. (2005), see 156225.0013.
In 8 patients with MDC1A (607855), Oliveira et al. (2008) identified a 5-kb deletion encompassing exon 56 of the LAMA2. Two patients were homozygous for the deletion, and 6 were compound heterozygous with another pathogenic LAMA2 mutation. The deletion was detected in 31% of 26 patients with the disorder. Although all patients were of Spanish or Portuguese descent, no common haplotypes were found.
In 2 sibs (patients 2 and 3) with autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23; 618138), Gavassini et al. (2011) identified compound heterozygous mutations in the LAMA2 gene: a c.728T-C transition in exon 5, resulting in a leu243-to-pro (L243P) substitution at a highly conserved residue in protein domain VI, and a complex splice site mutation in intron 33 (c.4860+2T-G_4860+3insGCC; 156225.0017), resulting in a splice site alteration, a frameshift, and premature termination (Phe1573_Lys1620delinsSerfsTer49). The splice site defect was confirmed by analysis of patient cells. Additional functional studies were not performed, but muscle biopsy showed partial LAMA2 deficiency. Expression of LAMA5 (601033) was increased.
For discussion of the complex splice site mutation in intron 33 of the LAMA2 gene (c.4860+2T-G_4860+3insGCC), resulting in a splice site alteration, a frameshift, and premature termination (Phe1573_Lys1620delinsSerfsTer49), that was found in compound heterozygous state in 2 sibs with autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23; 618138) by Gavassini et al. (2011), see 156225.0016.
In an 11-year-old girl with autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23; 618138), Chan et al. (2014) identified compound heterozygous mutations in the LAMA2 gene: a c.391C-T transition in exon 3, resulting in a gln131-to-ter (Q131X) substitution, and a c.4487C-T transition in exon 31, resulting in an ala1496-to-val (A1496V; 156225.0019) substitution. The Q131X mutation, which was inherited from the unaffected mother, occurred in domain VI of the protein, whereas the A1496V mutation, which was inherited from the unaffected father, occurred in domain IIIa of the protein. The patient also carried a heterozygous variant of unknown significance in the LAMA2 gene (C199S) that was inherited from the father. Functional studies of the variants were not performed, but skeletal muscle biopsy from the patient showed decreased LAMA2 in muscle fibers and in intramuscular motor nerves. Expression of LAMA5 (601033) was increased.
For discussion of the c.4487C-T transition in exon 31 of the LAMA2 gene, resulting in an ala1496-to-val (A1496V) substitution, that was found in compound heterozygous state in a patient with autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23; 618138) by Chan et al. (2014), see 156225.0018.
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