DES – Dilated Cardiomyopathy

Desmin (DES) is a type III intermediate filament protein critical for structural integrity and force transmission in cardiomyocytes. Heterozygous DES mutations have been implicated in autosomal dominant dilated cardiomyopathy (DCM) characterized by left ventricular dilation and systolic dysfunction. The association arises from multiple unrelated cases, familial segregation, and robust experimental data linking DES filament defects to DCM pathology.

Autosomal dominant inheritance is supported by heterozygous variants identified by whole exome sequencing in patients with isolated or familial DCM. A novel A285V missense variant was reported in 1 isolated proband (PMID:23300193) and predicted to disrupt desmin structure. A second heterozygous c.679C>T (p.Arg227Cys) variant cosegregated with disease in a Chinese pedigree (PMID:28171858). Sporadic and familial cases also include in‐frame deletions such as c.337_339del (p.Gln113_Leu115del) in two affected relatives with DCM and prominent left ventricular noncompaction (PMID:30908796).

Segregation analysis confirms DES pathogenicity: at least four additional affected relatives in the R227C family (PMID:28171858) and two in the Q113_L115del family (PMID:30908796). Additional sporadic cases include a L136P variant in a single family (PMID:26724190) and an I451M variant detected in three Japanese patients with DCM (PMID:11728149).

The variant spectrum spans missense substitutions clustering in the coiled‐coil rod domain (e.g., p.Arg227Cys, p.Ala285Val, p.Leu136Pro, p.Arg454Trp, p.Ile451Met) and small in‐frame deletions affecting filament assembly. No recurrent founder alleles have been described, and allele frequencies in control databases are negligible, supporting pathogenic roles.

Functional assays demonstrate a dominant‐negative mechanism. Patient‐derived iPSC cardiomyocytes expressing A285V-DES exhibit desmin aggregation and contractile deficits in vitro (PMID:23300193). Co‐transfection of mutant and wild-type DES in cell lines reveals impaired filament formation and cytoplasmic inclusions (PMID:26724190, PMID:30908796). Transgenic mice expressing a D7-des deletion display desmin aggregates, disrupted myofibril alignment, and blunted in vivo cardiac beta-agonist response (PMID:11352891). Early ES cell models show dose-dependent inhibition of cardiac and smooth muscle differentiation in desmin‐null lines (PMID:8612961).

Mechanistically, DES mutations disrupt intermediate filament assembly, leading to cytoskeletal collapse, aberrant gap junction remodeling, conduction slowing, and myocardial dysfunction. The cumulative genetic and experimental evidence supports a strong gene–disease validity for DES in DCM. DES variant testing enables molecular diagnosis, familial risk assessment, and may inform early intervention strategies.

Key take-home: Heterozygous DES mutations cause autosomal dominant DCM via a dominant-negative filament assembly defect, making DES sequencing clinically actionable for patients with unexplained DCM.

References

• Human molecular genetics • 2013 • Patient-specific induced-pluripotent stem cells-derived cardiomyocytes recapitulate the pathogenic phenotypes of dilated cardiomyopathy due to a novel DES mutation identified by whole exome sequencing. PMID:23300193
• Cardiology • 2017 • Exome Sequencing Identifies a Novel DES Mutation (R227C) in a Chinese Dilated Cardiomyopathy Family. PMID:28171858
• Human mutation • 2019 • Noncompaction cardiomyopathy is caused by a novel in-frame desmin (DES) deletion mutation within the 1A coiled-coil rod segment leading to a severe filament assembly defect. PMID:30908796
• Journal of molecular and cellular cardiology • 2016 • Functional characterization of the novel DES mutation p.L136P associated with dilated cardiomyopathy reveals a dominant filament assembly defect. PMID:26724190
• European heart journal • 2001 • Frequency and clinical characteristics of dilated cardiomyopathy caused by desmin gene mutation in a Japanese population. PMID:11728149
• Herz • 2000 • The "final common pathway" hypothesis and inherited cardiovascular disease. The role of cytoskeletal proteins in dilated cardiomyopathy. PMID:10904835
• Developmental biology • 1995 • Cytoskeletal control of myogenesis: a desmin null mutation blocks the myogenic pathway during embryonic stem cell differentiation. PMID:8612961
• Circulation • 2001 • Mouse model of desmin-related cardiomyopathy. PMID:11352891
• Journal of interventional cardiac electrophysiology • 2010 • Cardiac conduction disturbances and differential effects on atrial and ventricular electrophysiological properties in desmin deficient mice. PMID:20390331

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