title: FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. NALYACOUB@kfshrc.edu.sa.
authors.forename: Nadya
authors.initials: N
authors.lastname: Al-Yacoub
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. rshaheen@kfshrc.edu.sa.
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. smahmoud@kfshrc.edu.sa.
authors.forename: Salma Mahmoud
authors.initials: SM
authors.lastname: Awad
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. kunhi@kfshrc.edu.sa.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Kunhi
authors.affiliation: Cardiovascular & Pharmacogenetics, Genetics Department, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. dzimiri@kfshrc.edu.sa.
authors.forename: Nduna
authors.initials: N
authors.lastname: Dzimiri
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA. henry.c.nguyen@yale.edu.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Nguyen
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA. yong.xiong@yale.edu.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Heart Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. buraiki@kfshrc.edu.sa.
authors.forename: Jehad
authors.initials: J
authors.lastname: Al-Buraiki
authors.affiliation: King Saud University, Riyadh, 11211, Saudi Arabia. alhabeebw@yahoo.com.
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Habeeb
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. FAlKuraya@kfshrc.edu.sa.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. cpoizat99@kfshrc.edu.sa.
authors.forename: Coralie
authors.initials: C
authors.lastname: Poizat
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics* / Q000378:metabolism; D012518:Sarcomeres / Q000235:genetics / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases