FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy

• Published in: Genome Biology Vol. 17; no. 1; p. 2
• Main Authors: Al-Yacoub, Nadya, Shaheen, Ranad, Awad, Salma Mahmoud, Kunhi, Muhammad, Dzimiri, Nduna, Nguyen, Henry C, Xiong, Yong, Al-Buraiki, Jehad, Al-Habeeb, Waleed, Alkuraya, Fowzan S, Poizat, Coralie
• Format: Journal Article
• Language: English
• Published: England BioMed Central 11-01-2016
• Subjects: Amino Acid Sequence - genetics; Amino acids; Atrophy; Autophagy; Autophagy - genetics; Cardiomyopathy; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - pathology; Congestive heart failure; Cytoskeleton; Cytoskeleton - genetics; Cytoskeleton - metabolism; Dilated cardiomyopathy; Disease; F-box protein; Families & family life; Family medical history; Gene Expression Regulation; Genetic Linkage; Genetic Predisposition to Disease; Genomics; Heart failure; Heart Failure - genetics; Heart Failure - pathology; Humans; Immunoprecipitation; Missense mutation; Muscle Proteins - genetics; Muscle Proteins - metabolism; Musculoskeletal system; Mutation; Mutation, Missense - genetics; Patients; Phagocytosis; Proteins; Sarcomeres - genetics; Sarcomeres - metabolism; Siblings; SKP Cullin F-Box Protein Ligases - genetics; SKP Cullin F-Box Protein Ligases - metabolism; Transplants & implants
• ISSN: 1474-760X; 1474-7596; 1474-760X
• DOI: 10.1186/s13059-015-0861-4

Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy causing systolic dysfunction and heart failure. Rare variants in more than 30 genes, mostly encoding sarcomeric proteins and proteins of the cytoskeleton, have been implicated in familial DCM to date. Yet, the majority of variants causing DCM remain to be identified. The goal of the study is to identify novel mutations causing familial dilated cardiomyopathy.
We identify FBXO32 (ATROGIN 1), a member of the F-Box protein family, as a novel DCM-causing locus. The missense mutation affects a highly conserved amino acid and is predicted to severely impair binding to SCF proteins. This is validated by co-immunoprecipitation experiments from cells expressing the mutant protein and from human heart tissue from two of the affected patients. We also demonstrate that the hearts of the patients with the FBXO32 mutation show accumulation of selected proteins regulating autophagy.
Our results indicate that abnormal SCF activity with subsequent impairment of the autophagic flux due to a novel FBXO32 mutation is implicated in the pathogenesis of DCM.