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Published on: August 20, 2019
FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy
Nadya Al-Yacoub1, Ranad Shaheen2, Salma Mahmoud Awad3
1Cardiovascular Research Program, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Saudi Arabia. NALYACOUB@kfshrc.edu.sa.
Insights
Researchers identified a novel mutation in the FBXO32 gene causing familial dilated cardiomyopathy (DCM). This genetic finding impacts protein binding and impairs autophagy, contributing to heart failure pathogenesis.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Basis of Heart Disease
Background:
- Dilated cardiomyopathy (DCM) is a prevalent heart condition characterized by systolic dysfunction and heart failure.
- While over 30 genes are linked to familial DCM, many causative variants remain undiscovered.
- Identifying novel genetic mutations is crucial for understanding DCM's complex etiology.
Purpose of the Study:
- To identify novel genetic mutations responsible for familial dilated cardiomyopathy.
- To investigate the role of previously uncharacterized genes in DCM pathogenesis.
Main Methods:
- Genetic analysis to identify variants in familial DCM cases.
- Functional studies including co-immunoprecipitation to assess protein interactions.
- Analysis of patient heart tissue to examine protein accumulation and cellular processes.
Main Results:
- A novel missense mutation in the FBXO32 gene (encoding F-box protein 32, also known as Atrogin-1) was identified as a cause of DCM.
- The mutation impairs FBXO32 binding to SCF proteins, crucial for protein degradation.
- Patient hearts showed accumulation of proteins involved in autophagy, indicating impaired autophagic flux.
Conclusions:
- FBXO32 mutations represent a new genetic cause of dilated cardiomyopathy.
- Abnormal SCF activity and impaired autophagy due to FBXO32 mutations contribute to DCM development.
- This discovery offers new insights into the molecular mechanisms underlying familial heart failure.
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.
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