title: A substitution mutation in cardiac ubiquitin ligase, FBXO32, is associated with an autosomal recessive form of dilated cardiomyopathy.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  In a consanguineous family with four affected siblings with severe DCM, we combined homozygosity mapping, linkage analysis and WES, to uncover the genetic defect.
  
  
  RESULTS
  A 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Cardiovascular Genetics Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. zhassnan@kfshrc.edu.sa.|Deptartment of Medical Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. zhassnan@kfshrc.edu.sa.|College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. zhassnan@kfshrc.edu.sa.|Department of Medical Genetics, MBC-75, King Faisal Specialist Hospital & Research Centre, Takhassusi Street, PO Box 3354, Riyadh, 11211, Saudi Arabia. zhassnan@kfshrc.edu.sa.
authors.forename: Zuhair N
authors.initials: ZN
authors.lastname: Al-Hassnan
authors.affiliation: Cardiovascular Genetics Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Zarghuna Ma
authors.initials: ZM
authors.lastname: Shinwari
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Salma M
authors.initials: SM
authors.lastname: Wakil
authors.affiliation: Cardiovascular Genetics Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Sahar
authors.initials: S
authors.lastname: Tulbah
authors.affiliation: Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Shamayel
authors.initials: S
authors.lastname: Mohammed
authors.affiliation: Deptartment of Medical Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Zuhair
authors.initials: Z
authors.lastname: Rahbeeni
authors.affiliation: Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alghamdi
authors.affiliation: Cardiovascular Genetics Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Monther
authors.initials: M
authors.lastname: Rababh
authors.affiliation: Department of Biostatistics and Scientific Computing, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Dilek
authors.initials: D
authors.lastname: Colak
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Namik
authors.initials: N
authors.lastname: Kaya
authors.affiliation: Cardiovascular Genetics Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.|Heart Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Majid
authors.initials: M
authors.lastname: Al-Fayyadh
authors.affiliation: Heart Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Jehad
authors.initials: J
authors.lastname: Alburaiki
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D002874:Chromosome Mapping; D019295:Computational Biology; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D006321:Heart; D006720:Homozygote; D006801:Humans; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics*; D055815:Young Adult
chemical_list: D009124:Muscle Proteins; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases