LAMA2

Official Full Name

laminin subunit alpha 2

Organism

Homo sapiens

GeneID

3908

Background

Laminin, an extracellular protein, is a major component of the basement membrane. It is thought to mediate the attachment, migration, and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. It is composed of three subunits, alpha, beta, and gamma, which are bound to each other by disulfide bonds into a cross-shaped molecule. This gene encodes the alpha 2 chain, which constitutes one of the subunits of laminin 2 (merosin) and laminin 4 (s-merosin). Mutations in this gene have been identified as the cause of congenital merosin-deficient muscular dystrophy. Two transcript variants encoding different proteins have been found for this gene. [provided by RefSeq, Jul 2008]

Synonyms

LAMM; MDC1A;

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Detailed Information

Recent Progress

The laminin series of proteins are of considerable significance in research(Fig. 1). Mutations in the LAMA2 gene( the gene codes the laminin2 proteins) can lead to autosomal recessive laminin related congenital muscular dystrophy, more specifically, the congenital muscular dystrophy type 1A. This disease could result in multi-faceted secondary pathologies including inflammation, fibrosis, apoptosis, and necrosis leading to severe muscle weakness and minimal postnatal growth. Patients with partial laminin deficiency usually display milder phenotype than those with absent protein. Though the patients have structurally normal brains, they have increased risk of cerebral complications such as epilepsy and mental retardation, apart from the typical white matter abnormalities.

Fig. 1. xLNNd and laminin proteins. A. Construct design for chimeric hybrids consisting of β1, α1 and γ1 laminin LN-LEa domains fused to the nidogen-1 G2 through G3 domains. B. Recombinant α1β1γ1 laminins, wild-type (WT) and bearing an S68R point mutation or with α, β or γ1 mutations used in the study. C. Laminin polymerizes through the binding of α, β and γ LN domains, forming a ternary node complex. Laminins lacking any of the three LN domains are unable to polymerize. (McKee KK et al, 2018)

Researchers present a case with primary partial laminin deficiency resulting from a homozygous novel LAMA2 missense mutation. He developed West syndrome in his first year of life. A 5-year-old boy displayed global hypotonia with muscle weakness from birth. He presented infantile spasms and an EEG finding of hypsarrhythmia when aged 8 months. Seizures were controlled in a few weeks with intramuscular synthetic ACTH, then valproic acid was served. Antiepileptic medication was withdrawn two years later. Though the boy achieved unsupported walking at the age of 4, his cognitive status equals to a 2-year-old child. However, epilepsy has not recurred. Brain MRI displayed the typical white matter abnormalities without associated neuronal migration defects. This case report widens the clinical spectrum of cerebral manifestations related with mutations in LAMA2. Researchers also reported two patients with partial laminin deficiency and atypical phenotypes, one with almost exclusive central nervous system involvement and the other with marked cardiac dysfunction, rigid spine syndrome and limb-girdle weakness. Both these cases have two heterozygous LAMA2 variants with a potentially pathogenic missense mutation c.2461A>C (p.Thr821Pro) located in exon 18. The clinical phenotype of the patients is quite different from the typical type. This may be explained by the different combination of mutations types (two mis-sense versus a missense and a truncating mutation).

In order to implement a novel combinatorial treatment including losartan along with transgenic IGF-1 over-expression to improve postnatal growth. Researchers discovered that dual-therapy helps with inflammation and fibrosis, improved weight gain, and raised restoration of muscle architecture and locomotory function in DyW mice (mouse model of MDC1A). Using murine growth hormone, researchers further indicated that postnatal intervention with both therapies also produced considerable amelioration of dystrophic pathology. These findings taken together present a combinatorial anti-fibrotic and promyogenic therapy that could be the foundation of future therapies to a population of afflicted children in need.

It is demonstrated by the researchers that despite compensatory expression of laminin-α4, giving rise to Lm-411 (α4, β1, and γ1), muscle basement membrane is labile in LAMA2 MD biopsies. Through addition of two specifically designed linker proteins, polymerization and cell binding of Lm-411 could be enhanced. The first is called αLNNd and consists of the N-terminal part of laminin-α1 along with the laminin-binding site of nidogen-1. The second is called mini-agrin (mag) and contains binding sites for laminins and α-dystroglycan. Results showed that transgenic expression of mag and αLNNd in a mouse model for LAMA2 MD fully restored basement membrane stability, recovered muscle force and size, helped weight gain, and extended life span more than five times. These findings provide a strong basis for a potential treatment.

An eleven-year-old girl with early motor difficulties was also reported. Clinical assessment did not yield obvious clinical features. Muscle biopsy showed that the muscle had mildly dystrophic features and mildly depleted laminin α2 expression. The laminin α5 expression was diffusely upregulated, and depletion of laminin α2 in intramuscular motor nerves was observed. In the end, the patient was found to have autosomal recessively inherited double heterozygous LAMA2 mutations. This case indicated the mild end of the partial merosin deficiency phenotypic spectrum, and emphasized that careful assessment of laminin α2 expression in intramuscular motor nerves can be a helpful diagnostic clue in partial merosin deficiency.

References:

Camacho, Ana, et al. "LAMA2-related congenital muscular dystrophy complicated by West syndrome." European Journal of Paediatric Neurology 19.2(2015):243.
Marques, J, et al. "Atypical phenotype in two patients with LAMA2 mutations. " Neuromuscular Disorders 24.5(2014):419-424.
Accorsi, A, et al. "IGF-1/GH axis enhances losartan treatment in Lama2-related muscular dystrophy." Human Molecular Genetics 25.21(2016).
Reinhard, J. R., et al. "Linker proteins restore basement membrane and correct LAMA2-related muscular dystrophy in mice. " Science Translational Medicine 9.396(2017).
Chan, S. H., et al. "Limb girdle muscular dystrophy due to LAMA2 mutations: diagnostic difficulties due to associated peripheral neuropathy." Neuromuscular Disorders 24.8(2014):677-683.

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