Myofibrillar myopathy in the genomic context

Abstract

Myofibrillar myopathy (MFM) is a group of inherited muscular disorders characterized by myofibril dissolution and abnormal accumulation of degradation products. The diagnosis of muscular disorders based on clinical presentation is difficult due to phenotypic heterogeneity and overlapping symptoms. In addition, precise diagnosis does not always explain the disease etiopathology or the highly variable clinical course even among patients diagnosed with the same type of myopathy. The advent of high-throughput next-generation sequencing (NGS) has provided a successful and cost-effective strategy for identification of novel causative genes in myopathies, including MFM. So far, pathogenic mutations associated with MFM phenotype, including atypical MFM-like cases, have been identified in 17 genes: DES, CRYAB, MYOT, ZASP, FLNC, BAG3, FHL1, TTN, DNAJB6, PLEC, LMNA, ACTA1, HSPB8, KY, PYROXD1, and SQSTM + TIA1 (digenic). Most of these genes are also associated with other forms of muscle diseases. In addition, in many MFM patients, numerous genomic variants in muscle-related genes have been identified. The various myopathies and muscular dystrophies seem to form a single disease continuum; therefore, gene identification in one disease impacts the genetic etiology of the others. In this review, we describe the heterogeneity of the MFM genetic background focusing on the role of rare variants, the importance of whole genome sequencing in the identification of novel disease-associated mutations, and the emerging concept of variant load as the basis of the phenotypic heterogeneity.

Genetic and phenotypic characterisation of inherited myopathies in a tertiary neuromuscular centre

“…These include repeat expansion diseases, copy number variants and deep intronic mutations [21]. Oligogenic inheritance has also been speculated as a potential pathogenic mechanism [22] but this has not been explored in this study.…”

Drosophila NUAK functions with Starvin/BAG3 in autophagic protein turnover

“…Common proteins present in these aggregates include Filamin C (FILC), αB-crystallin (CRYAB), BAG3, and Desmin (DES), among others. The inability of MFM patients to clear these aggregates results in myofibrillar degeneration and a decline in muscle function [74][75][76][77][78][79][80]. Interestingly, mutations in Drosophila NUAK phenocopy both structural and functional deficits observed in MFM patients, including Fil and CryAB accumulation, muscle degeneration, and locomotor defects.…”

Whole-exome sequencing in patients with protein aggregate myopathies reveals causative mutations associated with novel atypical phenotypes

“…Clinical significance of these additional variants remains speculative and needs to be elucidated; they might contribute to the variability of the phenotype due to a synergistic or an antagonistic effect [43]. Alternatively, it has been suggested that the cumulative burden of variants might affect the functioning of target tissue modulating the penetrance and/or the expression of clinical phenotype [5].…”

“…MFM are usually transmitted as an autosomal dominant trait; however, X-linked, autosomal recessive and sporadic cases have been described [1][2][3][4]. Causative mutations have been identified in a minority of patients in one of the following genes: desmin (DES), αBcrystallin (CRYAB), myotilin (MYOT), Z-band alternatively spliced PDZ-containing protein (LBD3/ZASP), Bcl2-associated athanogene-3 (BAG3), and filamin C (FLNC) [1][2][3][4][5]. Recent mutations in FHL1, TTN, DNAJB6, PLEC, ACTA1, HSPB8, LMNA, KY, PYROXD1, and SQSTM1 have also been reported in patients featuring MFM pathology highlighting the variability and complexity of these muscular disorders [5].…”