LMNA – Dilated Cardiomyopathy

LMNA encodes the nuclear intermediate filament proteins lamins A and C. Heterozygous mutations in LMNA cause autosomal dominant dilated cardiomyopathy (DCM) with conduction defects and ventricular arrhythmias. The prevalence of LMNA variants in DCM cohorts ranges from 3.6% in idiopathic cases to 7.5% in familial DCM (PMID:18585512). Screening of 324 unrelated probands identified 19 protein‐altering LMNA variants including missense, nonsense, and splice‐site mutations. Clinical predictors of LMNA mutation carriage include supraventricular arrhythmia, conduction defects, and mild DCM phenotype (PMID:12628721).

Case reports and series have described multiple pedigrees spanning four generations. For example, the c.244G>A (p.Glu82Lys) variant segregated with disease in eight members of a Chinese family, four of whom were affected with DCM or ventricular dilation (PMID:16630578). Other recurrent variants include nonsense alleles (e.g., c.928C>T (p.Gln310Ter), c.961C>T (p.Arg321Ter)) and frameshifts, collectively establishing a broad spectrum of pathogenic mechanisms.

Segregation analysis across 49 families (269 individuals, 105 affected) demonstrated co‐segregation of LMNA mutations with DCM and conduction disease in multiple kindreds, with an estimated 19 additional affected relatives showing variant segregation (PMID:12628721). Variants cluster in the rod and tail domains, with both missense and truncating mutations disrupting lamina structure.

Functional studies provide mechanistic support. In HEK293 cells, p.Glu82Lys lamin A/C mislocalizes away from the inner nuclear membrane, induces emerin redistribution, and causes heterochromatin aggregation (PMID:16630578). A knock‐in mouse expressing the Lmna p.Asn195Lys variant recapitulates conduction defects and sudden death, with misexpression of connexins and sarcomeric disarray (PMID:15972724). These data concord with nuclear envelope fragility as a pathogenic mechanism.

No robust evidence disputes the LMNA–DCM association. However, incomplete penetrance and age‐related expressivity warrant longitudinal follow‐up. LMNA mutations predict poor prognosis, high risk of malignant ventricular arrhythmias, and may guide early ICD placement and family screening.

Key Take-home: LMNA mutations are a definitive cause of autosomal dominant DCM with conduction disease; genetic testing informs risk stratification and management.

References

• Journal of the American College of Cardiology • 2003 • Natural history of dilated cardiomyopathy due to lamin A/C gene mutations PMID:12628721
• Biochemical and biophysical research communications • 2006 • Mutation Glu82Lys in lamin A/C gene is associated with cardiomyopathy and conduction defect. PMID:16630578
• Human molecular genetics • 2005 • Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice. PMID:15972724
• American heart journal • 2008 • Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. PMID:18585512

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