期刊
JOURNAL OF CLINICAL MEDICINE
卷 9, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/jcm9040937
关键词
desmin; dilated cardiomyopathy; mitochondrial dysfunction; myopathy; non-ischemic cardiomyopathy; whole exome sequencing
资金
- Ministry of Health, Czech Republic [MZ AZV 15-27682A, NV19-08-00122, MZ AZV 17-28784A]
- Ministry of Health, Czech Republic - conceptual development of research organization (Institute for Clinical and Experimental Medicine - IKEM) [IN 00023001]
- Ministry of Health [RVO-VFN64165]
- Czech Academy of Sciences [RVO:67985823]
- National Center for Medical Genomics [LM2015091, CZ.02.1.01/0.0/0.0/16_013/0001634]
- Deutsche Stiftung fur Herzforschung (DSHF) [F07/17]
- Deutsche Forschungsgesellschaft (DFG) [MI-1146/2-2]
Background: The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. We aimed to describe the prevalence, phenotypic expression, and mitochondrial function of individuals with putative disease-causing desmin (DES) variants identified in patients with an unexplained etiology of cardiomyopathy. Methods: A total of 327 Czech patients underwent whole exome sequencing and detailed phenotyping in probands harboring DES variants. Results: Rare, conserved, and possibly pathogenic DES variants were identified in six (1.8%) probands. Two DES variants previously classified as variants of uncertain significance (p.(K43E), p.(S57L)), one novel DES variant (p.(A210D)), and two known pathogenic DES variants (p.(R406W), p.(R454W)) were associated with characteristic desmin-immunoreactive aggregates in myocardial and/or skeletal biopsy samples. The individual with the novel DES variant p.(Q364H) had a decreased myocardial expression of desmin with absent desmin aggregates in myocardial/skeletal muscle biopsy and presented with familial left ventricular non-compaction cardiomyopathy (LVNC), a relatively novel phenotype associated with desminopathy. An assessment of the mitochondrial function in four probands heterozygous for a disease-causing DES variant confirmed a decreased metabolic capacity of mitochondrial respiratory chain complexes in myocardial/skeletal muscle specimens, which was in case of myocardial succinate respiration more profound than in other cardiomyopathies. Conclusions: The presence of desminopathy should also be considered in individuals with LVNC, and in the differential diagnosis of mitochondrial diseases.
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