LMNA – dilated cardiomyopathy 1A

Lamin A/C, encoded by LMNA, is established as a cause of autosomal dominant dilated cardiomyopathy 1A (MONDO:0007269) with conduction system disease. Affected individuals present in adulthood with progressive left ventricular dilation, systolic dysfunction, arrhythmias and risk of sudden death. Family histories often reveal multiple affected relatives consistent with autosomal dominant inheritance and variable penetrance (PMID:20307303, PMID:25988045).

Case reports identified novel missense variants c.565C>T (p.Arg189Trp) in exon 3 (PMID:20307303) and c.569G>A (p.Arg190Gln) in unrelated heterozygotes with DCM and conduction defects (PMID:25988045). In a cohort of 324 unrelated probands, 19 carried protein‐altering LMNA variants (5.9% overall; 7.5% of familial DCM), encompassing 11 missense, 3 nonsense, 3 indels, and 1 splice‐site change, confirming a broad variant spectrum (PMID:18585512).

Functional studies reveal that AD LMNA mutations disrupt nuclear lamina assembly via haploinsufficiency and dominant‐negative effects. In vitro, rod‐domain mutants (e.g., N195K) induce aberrant lamin localization, emerin mislocalization and nuclear envelope aggregates. Tail‐domain mutations (e.g., R453W) impair emerin binding and lamina integrity (PMID:12783988). A knock‐in mouse expressing Lmna‐N195K recapitulates DCM‐CD1, showing arrhythmias, misexpression of connexins 40/43 and sarcomere disorganization (PMID:15972724).

Although some FDC pedigrees show incomplete co‐segregation and somatic mosaicism complicates interpretation (PMID:36526864), the preponderance of independent familial and functional data supports a definitive gene–disease relationship. LMNA variant carriers benefit from early surveillance for conduction defects and cardiomyopathy progression.

Key take-home: LMNA mutations cause autosomal dominant dilated cardiomyopathy 1A via lamina dysfunction; genetic testing guides early diagnosis, risk stratification and management.

References

• Cardiovascular ultrasound • 2010 • A novel LMNA mutation (R189W) in familial dilated cardiomyopathy: evidence for a 'hot spot' region at exon 3: a case report. PMID:20307303
• Oxford medical case reports • 2014 • LMNA-related dilated cardiomyopathy. PMID:25988045
• American heart journal • 2008 • Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. PMID:18585512
• 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
• Journal of cell science • 2003 • Effect of pathogenic mis-sense mutations in lamin A on its interaction with emerin in vivo. PMID:12783988

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