DES – Atrioventricular Block

The association between DES and Atrioventricular Block is supported by two unrelated patients. A de novo heterozygous missense variant c.1216C>T (p.Arg406Trp) was identified in a sporadic patient presenting with skeletal myopathy and atrioventricular conduction block requiring permanent pacing (PMID:10905661). A distinct homozygous recessive variant c.364T>C (p.Tyr122His) was found in a family with restrictive cardiomyopathy and concomitant atrioventricular block, absent from population databases and segregating with disease in a consanguineous pedigree (PMID:31718026). No additional segregation beyond the index cases has been reported.

Functional assays demonstrate that both p.Arg406Trp and p.Tyr122His disrupt desmin filament assembly. Expression of p.Arg406Trp in SW13 (vim–) cells yields aberrant aggregates and abolishes intermediate filament networks, consistent with a dominant-negative mechanism. Similarly, p.Tyr122His expressed in cardiomyocytes derived from induced pluripotent stem cells and HT-1080 cells causes severe filament assembly defects, confirming loss of network integrity (PMID:10905661; PMID:31718026). Collectively, these data support a limited clinical validity for DES in atrioventricular block, with moderate functional concordance. Key take-home: DES mutations can underlie atrioventricular conduction disease via desmin network disruption, informing genetic counseling and functional testing in affected individuals.

References

• Developmental biology • 1995 • Cytoskeletal control of myogenesis: a desmin null mutation blocks the myogenic pathway during embryonic stem cell differentiation. PMID:8612961
• Clinical genetics • 2000 • Sporadic cardiac and skeletal myopathy caused by a de novo desmin mutation. PMID:10905661
• Genes • 2019 • Restrictive Cardiomyopathy is Caused by a Novel Homozygous Desmin (DES) Mutation p.Y122H Leading to a Severe Filament Assembly Defect. PMID:31718026

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