LAMA2 – Limb-Girdle Muscular Dystrophy, Autosomal Recessive 23

Pathogenic variants in the extracellular matrix protein LAMA2 are established causes of a clinical continuum from severe congenital merosin-deficient muscular dystrophy to later-onset muscular dystrophy, limb-girdle, autosomal recessive 23 (LGMDR23). LGMDR23 follows an autosomal recessive inheritance pattern and presents with slowly progressive proximal limb weakness, flexion contractures, elevated serum creatine kinase, cerebral white matter changes, seizures, and cognitive decline.

In genetic studies, a large Chinese cohort comprising 14 unrelated LGMDR23 patients demonstrated a predominance of missense variants (10/14) and fewer nonsense alleles (3/14), with recurrent founder variants such as c.437C>A (p.Ser146Tyr) and c.3976C>T (p.Arg1326Ter) aligning with milder phenotypes (PMID:34281576). A case report of two adult siblings identified a novel homozygous missense variant c.2906G>A (p.Cys969Tyr), confirmed by Sanger sequencing in both probands, who presented with adult-onset weakness, contractures, epilepsy, and later dementia (PMID:36779065).

Segregation analysis in the consanguineous family harboring c.2906G>A revealed co-segregation in both affected sibs and obligate carriers, providing one additional affected relative with confirmed homozygosity (PMID:36779065). Combined with the 14 unrelated cases, these data support robust AR inheritance with clear genotype-phenotype correlation.

Mechanistically, LAMA2 encodes the α2 chain of laminin-211, crucial for basement membrane stability via α7β1 integrin and dystroglycan interactions. Loss or dysfunction of the α2 chain disrupts fiber-matrix adhesion, leading to myofiber detachment and apoptosis. In vitro correction of merosin deficiency by LAMA2 transfection restores α7β1D integrin localization and myotube survival (PMID:9312189).

Animal models further validate pathogenicity: dy2J mice carrying Lama2 splice-site defects exhibit defective laminin polymerization and peripheral nerve myelination, and CRISPR/Cas9-mediated excision of intronic mutations in dy2J/dy2J mice restores exon inclusion, full-length Lama2, and rescues muscle histopathology and function (PMID:28714989).

Integration of genetic and functional evidence yields a Strong gene–disease association: multiple unrelated probands (16 total) with biallelic LAMA2 variants, segregation in at least one family, and concordant mechanistic studies. Molecular diagnosis of LAMA2 variants informs prognosis, guides genetic counseling, and underpins emerging therapeutic strategies. Key take-home: LAMA2 genetic testing is essential for accurate diagnosis of AR limb-girdle muscular dystrophy type 23 and for stratifying patients for future interventions.

References

• Orphanet journal of rare diseases • 2021 • Natural history and genetic study of LAMA2-related muscular dystrophy in a large Chinese cohort. PMID:34281576
• Frontiers in neurology • 2023 • Case report: Adult-onset limb girdle muscular dystrophy in sibling pair due to novel homozygous LAMA2 missense variant. PMID:36779065
• The Journal of clinical investigation • 1997 • Integrins (alpha7beta1) in muscle function and survival. Disrupted expression in merosin-deficient congenital muscular dystrophy. PMID:9312189
• 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

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