LAMA2 – congenital merosin-deficient muscular dystrophy 1A

Laminin α2, encoded by LAMA2 (HGNC:6482), is essential for basement membrane stability in skeletal muscle and central nervous system. Biallelic pathogenic variants in LAMA2 cause autosomal recessive congenital merosin-deficient muscular dystrophy type 1A (MDC1A), characterized by early hypotonia, progressive muscle weakness, and cerebral white matter abnormalities (Gene Symbol; Disease Name).

Genetic Evidence

MDC1A follows an autosomal recessive inheritance pattern. Segregation analysis in a family with late-onset limb-girdle weakness identified three additional affected siblings sharing LAMA2 linkage (PMID:9131648), and further familial studies corroborate segregation in multiple pedigrees. A cohort of 26 unrelated MDC1A patients showed a 96% mutation detection rate across 52 alleles, including a recurrent exon 56 deletion in 31% of cases (PMID:18700894).

Variant Spectrum

Pathogenic alleles span the full gene, predominated by loss-of-function variants: nonsense, frameshift, splice-site, and large deletions. Missense changes are less common and often associated with milder, late-onset phenotypes. A notable example is the stop-gain variant c.7147C>T (p.Arg2383Ter) in exon 50 (PMID:24223650), reported in classical and attenuated presentations.

Functional Evidence

Integrin α7β1 localization and myotube survival are disrupted in merosin-deficient human myoblasts and restored by LAMA2 transfection, defining integrins as merosin receptors (PMID:9312189). In zebrafish, lama2 splice-site mutants exhibit muscle fiber detachment without sarcolemmal rupture and brain growth defects, modeling MDC1A pathology (PMID:22952766). In dy2J/dy2J mice, CRISPR-Cas9 correction of a Lama2 splice mutation via nonhomologous end joining restores exon inclusion and full-length protein, improving muscle function (PMID:28714989).

Conflicting Evidence

No substantial conflicting or refuting reports have been published. Partial laminin α2 expression correlates with milder phenotypes but does not dispute the gene-disease link.

Integration & Clinical Utility

Robust genetic and experimental data define a definitive association between LAMA2 and MDC1A. Diagnostic sequencing of LAMA2—coupled with immunohistochemical merosin assessment—should be pursued in infants and children presenting with hypotonia, elevated creatine kinase, and white matter changes. Early molecular confirmation informs prognosis, genetic counseling, and emerging gene or protein replacement therapies.

Key Take-home: MDC1A is a definitive autosomal recessive disorder driven by LAMA2 loss-of-function variants, with clear diagnostic markers and validated cellular and animal models guiding precision care.

References

• Neuromuscular disorders • 1997 • Late onset muscular dystrophy with cerebral white matter changes due to partial merosin deficiency. PMID:9131648
• Clinical genetics • 2008 • LAMA2 gene analysis in a cohort of 26 congenital muscular dystrophy patients. PMID:18700894
• Experimental and therapeutic medicine • 2013 • Merosin-deficient congenital muscular dystrophy type 1A: A case report. PMID:24223650
• PloS one • 2012 • A splice site mutation in laminin-α2 results in a severe muscular dystrophy and growth abnormalities in zebrafish. PMID:22952766
• 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
• The Journal of clinical investigation • 1997 • Integrins (alpha7beta1) in muscle function and survival. Disrupted expression in merosin-deficient congenital muscular dystrophy. PMID:9312189

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