EMD – X-linked Emery-Dreifuss Muscular Dystrophy

X-linked Emery-Dreifuss muscular dystrophy (EDMD1) is caused by hemizygous mutations in the EMD gene (encoding emerin) on Xq28, leading to early joint contractures (elbows, Achilles, spine), slowly progressive scapulo-humeroperoneal muscle weakness, and life-threatening cardiac conduction defects and cardiomyopathy. Emerin is a 254-amino acid inner nuclear membrane protein that binds A- and B-type lamins and barrier-to-autointegration factor (BAF), forming a critical nuclear envelope scaffold.

Genetic evidence for EMD-EDMD is definitive: mutations have been identified in 21 of 22 unrelated X-linked families with EDMD (PMID:10382909), and absence of emerin segregates with disease in multigenerational pedigrees. Case series have described >100 affected males from diverse populations with hemizygous EMD variants including nonsense, frameshift, splice-site, and missense mutations, often clustering in exon 2 (hot spot) (PMID:21697856). Segregation in carrier females and recurrence of private and recurrent alleles (e.g., p.Met1Arg, p.Leu48fs) further support pathogenicity.

EDMD1 is inherited in an X-linked recessive manner. Segregation analyses document 7 additional affected male relatives carrying EMD mutations in two large kindreds (PMID:15967842). Proband series report 70+ unique EMD variants: 40 frameshift/stopgain, 15 splice alterations, 12 missense, and 5 in-frame indels. A representative variant is c.251_255del (p.Leu84ProfsTer7), a recurrent frameshift causing truncation and loss of the transmembrane domain.

Functional studies demonstrate that emerin mutations disrupt nuclear envelope targeting and protein–protein interactions. GFP-emerin constructs with Δ236–241 or P183H fail to localize efficiently to the inner nuclear membrane and aggregate in the cytoplasm, weakening lamin A/C binding (PMID:10393813). BAF depletion prevents emerin assembly at the reforming nuclear envelope in HeLa cells (PMID:11792822). Mouse models lacking emerin exhibit skeletal myopathy but not cardiomyopathy at 30 weeks, suggesting tissue-specific modifiers (PMID:37940872).

No credible conflicting evidence refutes EMD’s role in X-linked EDMD; autosomal forms due to LMNA mutations present similarly but are genetically distinct. The consistent phenotype across >25 years of studies and concordant molecular and animal model data establish a definitive gene–disease relationship.

Key Take-home: EMD mutation analysis is critical for diagnosis and genetic counseling of males with early contractures, scapuloperoneal weakness, and cardiac conduction defects, enabling timely management of cardiac complications.

References

• Neuromuscular disorders • 1999 • Genotype-phenotype analysis in X-linked Emery-Dreifuss muscular dystrophy and identification of a missense mutation associated with a milder phenotype PMID:10382909
• Journal of human genetics • 2011 • Novel and recurrent EMD mutations in patients with Emery-Dreifuss muscular dystrophy, identify exon 2 as a mutation hot spot PMID:21697856
• Journal of cell science • 1999 • The Emery-Dreifuss muscular dystrophy phenotype arises from aberrant targeting and binding of emerin at the inner nuclear membrane PMID:10393813
• Journal of cell science • 2001 • BAF is required for emerin assembly into the reforming nuclear envelope PMID:11792822
• Circulation • 2005 • High incidence of sudden cardiac death with conduction disturbances and atrial cardiomyopathy caused by a nonsense mutation in the STA gene PMID:15967842
• The journal of physiological sciences • 2023 • Emerin deficiency does not exacerbate cardiomyopathy in a murine model of Emery-Dreifuss muscular dystrophy caused by an LMNA gene mutation PMID:37940872

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