Abstract
BackgroundFamilial dilated cardiomyopathy (DCM) is genetically heterogeneous. Mutations in more than 40 genes have been identified in familial cases, mostly inherited in an autosomal dominant pattern. DCM due to recessive mutations is rarely observed. In consanguineous families, homozygosity mapping and whole exome sequencing (WES) can be utilized to identify the genetic defects in recessively inherited DCM.MethodsIn a consanguineous family with four affected siblings with severe DCM, we combined homozygosity mapping, linkage analysis and WES, to uncover the genetic defect.ResultsA region of homozygosity (ROH) on chromosome 8q24.13–24.23 was found to be shared by all of the four affected siblings. WES detected ~47,000 variants that were filtered to a homozygous mutation (p.Gly243Arg) in the FBXO32 gene, located within the identified ROH. The mutation segregated with the phenotype, replaced a highly-conserved amino acid, and was not detected in 1986 ethnically-matched chromosomes. FBXO32, which encodes a muscle-specific ubiquitin ligase, has been implicated in the pathogenesis of cardiomyopathy through the ubiquitin proteasome system (UPS). In addition, FBXO32-knockout mice manifest with cardiomyopathy. Screening the index patient for all of the WES variants in 48 genes known to be implicated in hypertrophic and dilated cardiomyopathy was negative.ConclusionsOur data suggest that FBXO32 is a candidate gene for recessive DCM. Acting as a cardiac ubiquitin ligase, mutated FBXO32 could perturb the degradation of target proteins in the UPS, the impairment of which has been observed in cardiomyopathy. Our work proposes that genes encoding other ubiquitin ligases could also be implicated in familial cardiomyopathy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-016-0267-5) contains supplementary material, which is available to authorized users.
Highlights
Familial dilated cardiomyopathy (DCM) is genetically heterogeneous
The results of linkage analysis and homozygosity mapping were useful in restricting the analysis to the single region of homozygosity (ROH) that had been identified to be shared by all the affected individuals
The extended ROH on chromosome 8q24 was found to have 437 homozygous variants across the 17 Mb region. These variants were further filtered by excluding reported polymorphisms in the dbSNP and 1000 Genomes databases, resulting in only two homozygous variants; p.His356Tyr in OC90 and p.Gly243Arg in FBXO32
Summary
Familial dilated cardiomyopathy (DCM) is genetically heterogeneous. Mutations in more than 40 genes have been identified in familial cases, mostly inherited in an autosomal dominant pattern. A familial pattern, mostly inherited as autosomal dominant, has been observed in about 20–35 % of DCM cases with remarkable genetic heterogeneity; disease-associated mutations have been identified in more than 40 genes [3, 4]. A recessively inherited form of familial DCM is rarely observed and is often associated with extra-cardiac manifestations such as skeletal myopathy, hypotonia, hepatic encephalopathy, and impaired fatty acid oxidation defects. The protein encoded by FBXO32, known as atrogin-1 and MAFbx, is an E3 ligase that is expressed selectively in skeletal muscles and cardiomyocytes and plays a critical role in muscle atrophy [8, 9], as well as in the development of cardiac hypertrophy and atrophy [10, 11]. In support of an association between deficient FBXO32 protein and CMP, a recent study has shown that atrogin-1 knockout mice develop CMP with intracellular protein accumulation and cardiomyocyte apoptosis [12]
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