DES – Myofibrillar Myopathy 1

Desmin, encoded by DES, is a type III intermediate filament protein critical for the structural integrity of cardiac, skeletal, and smooth muscle. Pathogenic variants in DES cause myofibrillar myopathy 1, a disorder characterized by progressive skeletal muscle weakness, cardiomyopathy, and conduction defects. The hallmark pathology is cytoplasmic desmin-positive aggregates in muscle fibres, reflecting impaired filament assembly and maintenance.

Extensive genetic studies demonstrate an autosomal dominant inheritance mode with high penetrance. Segregation analysis in multiple families, including a four-generation pedigree with 16 affected members, supports dominant transmission and co-segregation of DES variants with disease (PMID:23051780). A meta-analysis of 159 mutation carriers across 40 unique variants, including 11 multiplex families and sporadic cases, further confirms the gene–disease link (PMID:20718792).

The variant spectrum is dominated by missense substitutions clustering in the rod domain (e.g., c.1217G>C (p.Arg406Pro) and c.1034T>C (p.Leu345Pro)), with additional splice‐site, in-frame deletions, and rare loss-of-function alleles reported. Recurrent hotspot mutations include p.Arg406Trp/Gln/Pro (PMID:14991347) and p.Ser13Phe (PMID:17720647). Compound heterozygous loss-of-function variants also underlie autosomal recessive forms, broadening the pathogenic mechanisms.

Functional assays in cell models and animal studies reveal a dominant-negative mechanism for many missense mutations. Expression of mutant desmin in SW13 and HeLa cells disrupts filament networks, causing aggregate formation (PMID:10545598). Transgenic mice expressing a 7-amino-acid deletion develop cardiac aggregates and impaired β-adrenergic response (PMID:11352891), whereas desmin null mutants demonstrate failed skeletal myogenesis (PMID:8612961).

A subset of variants in the alpha-helical rod, such as p.Ala213Val and p.Ala360Pro, exhibit conditional pathogenicity and may require additional factors to manifest disease (PMID:16865695). No studies have refuted the core desmin–myofibrillar myopathy association, though variable expressivity and incomplete penetrance warrant careful genetic counselling.

Integration of genetic and experimental data supports a Strong ClinGen classification for DES–myofibrillar myopathy 1. Genetic testing for DES variants enables early diagnosis and surveillance for cardiomyopathy and conduction defects, guiding prophylactic device placement and family screening. Key Take-home: DES mutation screening is clinically actionable for risk stratification and management of skeletal and cardiac manifestations.

References

• The New England Journal of Medicine • 2000 • Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. PMID:10717012
• Clinical genetics • 2011 • Desmin-related myopathy. PMID:20718792
• European neurology • 2012 • Clinical and myopathological characteristics of desminopathy caused by a mutation in desmin tail domain. PMID:23051780
• Journal of neurology • 2004 • A series of West European patients with severe cardiac and skeletal myopathy associated with a de novo R406W mutation in desmin. PMID:14991347
• European journal of medical genetics • 2007 • Two related Dutch families with a clinically variable presentation of cardioskeletal myopathy caused by a novel S13F mutation in the desmin gene. PMID:17720647
• Developmental biology • 1995 • Cytoskeletal control of myogenesis: a desmin null mutation blocks the myogenic pathway during embryonic stem cell differentiation. PMID:8612961
• Human molecular genetics • 1999 • A missense mutation in the desmin rod domain is associated with autosomal dominant distal myopathy, and exerts a dominant negative effect on filament formation. PMID:10545598
• Circulation • 2001 • Mouse model of desmin-related cardiomyopathy. PMID:11352891
• Human mutation • 2006 • Variable pathogenic potentials of mutations located in the desmin alpha-helical domain. PMID:16865695

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