ClinicalGeneticSevere cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene
Introduction
The DES gene encodes desmin, which is a major intermediate filament protein of skeletal and cardiac muscle that provides structural and functional integrity by coordinating mechanical stress transmission, organelle positioning, organization and assembly of sarcomeres, signal transduction, and apoptosis.1 Mutations in the DES gene are associated with a variable clinical phenotype referred to as desmin-related myopathy (OMIM #601419). The clinical phenotype encompasses “isolated” myopathies, pure cardiac phenotypes (including dilated cardiomyopathy [DCM] and restrictive cardiomyopathy [RCM]), cardiac conduction disease, and combinations of these disorders.2, 3, 4, 5, 6, 7, 8, 9, 10 If both cardiologic and neurologic features occur, they can manifest in any order, as cardiologic features can precede, occur simultaneously with, or follow manifestation of generalized neuromuscular disease.
More than 40 DES mutations have been identified in 53 different index patients. The majority of mutations are located in the α-helical rod domains of the gene. Potential genotype–phenotype relationships are emerging. It has recently been suggested that mutations in the 2B segment of desmin are mainly involved in skeletal muscle disease, whereas mutations in the 1B and tail domain cause more serious cardiac disease.11
We have identified five Dutch families, two of which have recently been partially described, with a variable yet predominantly cardiologic phenotype among individuals carrying an identical missense mutation in the head domain of the DES gene.12
The aim of this study was to investigate (1) the impressive phenotypic variability in the largest series of patients with a single DES mutation that is located in the head domain (p.S13F); (2) the occurrence of right-sided myocardial involvement including arrhythmogenic right ventricular cardiomyopathy (ARVC)-like phenotypes; and (3) the effect of the p.S13F mutation on cell–junction organization.
Section snippets
Clinical evaluation
The five index patients were referred to our cardiogenetics outpatient clinic, UMC Groningen, with either a primary cardiologic phenotype (two index patients) or a neurologic phenotype associated with cardiac manifestations (three index patients). Two of the index patients were recently described.12 The index patients and their relatives underwent a regular clinical genetic counseling procedure. Patients who gave informed consent were evaluated for cardiologic and/or neurologic and genetic
Phenotypic description
Detailed clinical data of all individual DES 38C>T mutation or obligate carrier patients and those likely to be affected, including outcomes and results of previous histology, are given in Table 1. The pedigrees are shown in Figure 1. The clinical criteria for two patients who met the criteria for ARVC are given in Table 2. Results of clinical evaluation were available for 22 individuals from the five families, and limited information was available for another five patients who were obligate
Discussion
Disease-associated DES mutations are generally located in the α-helical domain of desmin, and only five mutations in the N-terminal head domain have been described to date.2, 10, 24, 25 The head domain is believed to be important for aggregation of tetramers to fibers (assembly) and for stability of the protein. Interaction with the outer cellular membrane occurs through the desmosome where desmin interacts with several proteins such as desmoplakin.1, 26 The assembly state of desmin seems to
Conclusion
This report describes the largest series to date of 27 patients with a single head domain desmin mutation. The associated phenotype is fully penetrant. Patients demonstrated a highly variable yet predominantly cardiologic clinical picture of right-sided myocardial involvement (including the diagnosis of ARVC), RBBB, and/or ventricular tachycardias originating from the RV during the early phases of the disease. Males manifested disease at an earlier age than did females. Some of the families
Acknowledgements
We thank the patients who participated in this study and our colleagues who referred patients and supplied additional information. We thank Jackie Senior (editing), Eric Hennekam (genealogy), and Marian Claessens (haplotyping) for assistance.
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