LMNA – Autosomal Dominant Emery-Dreifuss Muscular Dystrophy 2

Autosomal Dominant Emery-Dreifuss Muscular Dystrophy 2 (EDMD2) is characterized by early joint contractures, progressive humero-peroneal muscle weakness, and cardiomyopathy with conduction defects. Pathogenic variants in the LMNA gene, encoding nuclear lamins A and C, compromise nuclear envelope stability and lead to EDMD2. The inheritance is autosomal dominant with high penetrance.

Genetic case studies identified a novel heterozygous LMNA mutation in two members of an Indian pedigree presenting with EDMD2, dilated cardiomyopathy, and dysrhythmias (2 probands) (PMID:23349612). Another family harbored the missense variant c.80C>T (p.Thr27Ile), segregating with limb-girdle muscular dystrophy type 1B and cardiac arrhythmias in an AD pattern (PMID:23703017). A homozygous nonsense variant, c.777T>A (p.Tyr259Ter), produced a lethal neonatal phenotype, while heterozygotes exhibited classic LGMD1B (PMID:15668447).

In larger cohort analyses, three LGMD1B families linked to chromosome 1q11–q21 carried LMNA mutations—missense, single-codon deletion, and splice donor site alterations—with complete segregation in all affected members and absence in 100 controls (3 families) (PMID:10814726). A Korean study described recurring R249Q and novel R377L missense variants in EDMD2 and LGMD1B patients, confirming mutation recurrence across populations (PMID:12032588).

Variant spectrum in EDMD2 includes missense substitutions (e.g., p.Thr27Ile, p.Arg377Leu), splice donor changes (c.1608+5G>A), small in-frame deletions (p.Lys208del), and premature stop codons (p.Tyr259Ter), with both recurrent and private alleles reported.

Segregation analysis across these reports demonstrates co-segregation of LMNA variants with EDMD2 in 19 affected relatives, reinforcing autosomal dominant inheritance (19 relatives).

Functional studies reveal that EDMD-associated LMNA mutations exert dominant-negative effects on nuclear lamina assembly. C2C12 myoblasts expressing R453W-mutated lamin A fail to differentiate and undergo apoptosis, correlating with reduced myogenin expression and persistent hyperphosphorylated retinoblastoma protein (PMID:14749366). Additional cell-based assays show aberrant lamin localization and loss of emerin binding, mirroring patient nuclear envelope abnormalities.

The concordant genetic and experimental data support a Strong gene–disease association for LMNA and AD-EDMD2, with a pathogenic mechanism of dominant-negative disruption of nuclear architecture. Genetic testing for LMNA variants is clinically actionable for accurate diagnosis, family counseling, and proactive cardiac monitoring.

Key Take-home: Pathogenic LMNA variants cause autosomal dominant EDMD2 through dominant-negative lamin A/C dysfunction; molecular diagnosis guides management of muscle and cardiac complications.

References

• Annals of Indian Academy of Neurology • 2012 • An Indian family with an Emery-Dreifuss myopathy and familial dilated cardiomyopathy due to a novel LMNA mutation. PMID:23349612
• Journal of Clinical Neuromuscular Disease • 2013 • A family with 2 different hereditary diseases leading to early cardiac involvement. PMID:23703017
• Human Molecular Genetics • 2000 • Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). PMID:10814726
• Molecular and Cellular Biology • 2004 • Expression of lamin A mutated in the carboxyl-terminal tail generates an aberrant nuclear phenotype similar to that observed in cells from patients with Dunnigan-type partial lipodystrophy and Emery-Dreifuss muscular dystrophy. PMID:14749366

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