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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
Author(s) -
Marakhonov Andrey V.,
Brodehl Andreas,
Myasnikov Roman P.,
Sparber Peter A.,
Kiseleva Anna V.,
Kulikova Olga V.,
Meshkov Alexey N.,
Zharikova Anastasia A.,
Koretsky Serguey N.,
Kharlap Maria S.,
Stanasiuk Caroline,
Mershina Elena A.,
Sinitsyn Valentin E.,
Shevchenko Alexey O.,
Mozheyko Natalia P.,
Drapkina Oksana M.,
Boytsov Sergey A.,
Milting Hendrik,
Skoblov Mikhail Yu.
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23747
Subject(s) - desmin , intermediate filament , biology , mutation , mutant , myopathy , cardiomyopathy , microbiology and biotechnology , genetics , gene , medicine , vimentin , immunohistochemistry , heart failure , cytoskeleton , cell , immunology
Mutations in DES , encoding desmin protein, are associated with different kinds of skeletal and/or cardiac myopathies. However, it is unknown, whether DES mutations are associated with left ventricular hypertrabeculation (LVHT). Here, we performed a clinical examination and subsequent genetic analysis in a family, with two individuals presenting LVHT with conduction disease and skeletal myopathy. The genetic analysis revealed a novel small in‐frame deletion within the DES gene, p.Q113_L115del, affecting the α‐helical rod domain. Immunohistochemistry analysis of explanted myocardial tissue from the index patient revealed an abnormal cytoplasmic accumulation of desmin and a degraded sarcomeric structure. Cell transfection experiments with wild‐type and mutant desmin verified the cytoplasmic aggregation and accumulation of mutant desmin. Cotransfection experiments were performed to model the heterozygous state of the patients and revealed a dominant negative effect of the mutant desmin on filament assembly. DES:p.Q113_L115del is classified as a pathogenic mutation associated with dilated cardiomyopathy with prominent LVHT.