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Genome Biol. 2016 Jan 11;17:2. doi: 10.1186/s13059-015-0861-4.

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

Author information

1
Cardiovascular Research Program, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. NALYACOUB@kfshrc.edu.sa.
2
Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. rshaheen@kfshrc.edu.sa.
3
Cardiovascular Research Program, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. smahmoud@kfshrc.edu.sa.
4
Cardiovascular Research Program, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. kunhi@kfshrc.edu.sa.
5
Cardiovascular & Pharmacogenetics, Genetics Department, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. dzimiri@kfshrc.edu.sa.
6
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA. henry.c.nguyen@yale.edu.
7
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA. yong.xiong@yale.edu.
8
Heart Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. buraiki@kfshrc.edu.sa.
9
King Saud University, Riyadh, 11211, Saudi Arabia. alhabeebw@yahoo.com.
10
Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. FAlKuraya@kfshrc.edu.sa.
11
Cardiovascular Research Program, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. cpoizat99@kfshrc.edu.sa.

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.

CONCLUSION:

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.

PMID:
26753747
PMCID:
PMC4707779
DOI:
10.1186/s13059-015-0861-4
[Indexed for MEDLINE]
Free PMC Article

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