LAMA2 – LAMA2-related muscular dystrophy

LAMA2 (HGNC:6482) encodes the α2 chain of laminin-211, a key component of the muscle basement membrane. Biallelic pathogenic variants in LAMA2 cause autosomal recessive LAMA2-related muscular dystrophy ([MONDO:0100228]), whose spectrum ranges from severe congenital forms with hypotonia and white matter changes to milder limb-girdle presentations with later onset and partial merosin deficiency.

Genetically, over 230 unrelated probands have been reported to harbor pathogenic LAMA2 variants, including homozygous and compound heterozygous changes across all domains of the gene. A representative variant is c.5116C>T (p.Arg1706Ter) (PMID:25332755), identified by next-generation sequencing in a preimplantation diagnostic setting. Large cohorts include 130 Chinese patients (PMID:34281576), 27 international cases in a whole-body MRI study (PMID:34559299), and 52 Brazilian patients with CNS involvement (PMID:37182895).

The variant spectrum encompasses over 140 distinct pathogenic alleles: more than 80 loss-of-function (nonsense, frameshift or splice‐site) and >40 missense changes (PMID:34281576). Deep intronic splice‐activating variants have been described (e.g., NM_000426.4:c.3038-7G>A) (PMID:38691940), and copy-number variants account for up to 26%–50% of alleles in certain cohorts. Population‐specific alleles include a founder nonsense variant (c.2901C>A (p.Cys967Ter)) in Albanian families (PMID:16216942). Segregation with disease has been demonstrated in affected sibpairs (2 affected relatives) (PMID:26304763).

Functional studies confirm that loss of merosin leads to mislocalization of α7β1 integrins and myotube apoptosis in vitro (PMID:9312189). In dy2J mice, the laminin α2 subunit polymerization defect yields basement membrane instability and muscle weakness (PMID:10574769). The zebrafish candyfloss (caf) mutant recapitulates fiber detachment without initial sarcolemmal rupture, underscoring a mechanical adhesion failure mechanism (PMID:17438294).

Restoration of laminin function has been achieved by merosin α2 chain transfection, which corrects integrin localization and enhances myotube survival. In dy2J/dy2J mice, CRISPR-Cas9 NHEJ editing of a splice‐site mutation rescues exon inclusion and improves muscle histopathology and function (PMID:28714989). Recombinant human laminin-111 and laminin-211 protein therapy in immunodeficient dyW mice ameliorates muscle disease progression, validating protein replacement approaches (PMID:32498713).

Taken together, the abundant genetic and experimental evidence provides definitive support for LAMA2 as the causative gene in LAMA2-related muscular dystrophy. Clinical genetic testing enables early diagnosis, informs reproductive planning, and guides management. Key take-home: comprehensive LAMA2 variant analysis is critical for accurate diagnosis and therapeutic development in merosin-deficient muscular dystrophy.

References

• Journal of prenatal medicine • 2014 • Next generation sequencing in the identification of a rare genetic disease from preconceptional couple screening to preimplantation genetic diagnosis. PMID:25332755
• Brain & development • 2016 • Clinical and molecular genetic analysis of a family with late-onset LAMA2-related muscular dystrophy. PMID:26304763
• Journal of neurology • 2022 • Diagnostic interest of whole-body MRI in early- and late-onset LAMA2 muscular dystrophies: a large international cohort. PMID:34559299
• Orphanet journal of rare diseases • 2021 • Natural history and genetic study of LAMA2-related muscular dystrophy in a large Chinese cohort. PMID:34281576
• Journal of neuromuscular diseases • 2023 • Brain MRI Abnormalities, Epilepsy and Intellectual Disability in LAMA2 Related Dystrophy - a Genotype/Phenotype Correlation. PMID:37182895
• Neuromuscular disorders : NMD • 2024 • A novel deep intronic variant in LAMA2 identified by RNA sequencing. PMID:38691940
• Archives of neurology • 2005 • LAMA2 gene analysis in congenital muscular dystrophy: new mutations, prenatal diagnosis, and founder effect. PMID:16216942
• The Journal of clinical investigation • 1997 • Integrins (alpha7beta1) in muscle function and survival. Disrupted expression in merosin-deficient congenital muscular dystrophy. PMID:9312189
• Current biology : CB • 1999 • The laminin alpha2 expressed by dystrophic dy(2J) mice is defective in its ability to form polymers. PMID:10574769
• Proceedings of the National Academy of Sciences of the United States of America • 2007 • The zebrafish candyfloss mutant implicates extracellular matrix adhesion failure in laminin alpha2-deficient congenital muscular dystrophy. PMID:17438294
• Nature medicine • 2017 • Correction of a splicing defect in a mouse model of congenital muscular dystrophy type 1A using a homology-directed-repair-independent mechanism. PMID:28714989
• Skeletal muscle • 2020 • Human laminin-111 and laminin-211 protein therapy prevents muscle disease progression in an immunodeficient mouse model of LAMA2-CMD. PMID:32498713

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