FBXO32 – Dilated Cardiomyopathy

Familial dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and systolic dysfunction leading to heart failure. FBXO32 (F-box only protein 32) encodes a muscle-specific E3 ubiquitin ligase involved in proteasomal degradation and autophagy. Rare pathogenic variants in FBXO32 have emerged as a novel cause of autosomal recessive DCM. This summary reviews genetic and functional data supporting a strong clinical validity for the FBXO32–DCM association.

Genetic evidence supports autosomal recessive inheritance with multiple affected siblings in consanguineous families. A homozygous missense mutation p.Gly243Arg segregated with disease in four siblings (homozygous probands) and was absent in 1,986 control chromosomes (PMID:26768247). Additionally, two unrelated probands harboring a conserved missense variant demonstrated impaired SCF binding (PMID:26753747). In total, six probands across two families exhibit co-segregation of FBXO32 variants ([PMID:26753747]; [PMID:26768247]). A recurrent in-frame deletion c.884_886del (p.Lys295del) was also identified in an Iranian kindred with recessive DCM (PMID:36344977).

Functional studies elucidate a loss-of-function mechanism. Co-immunoprecipitation from patient heart tissue and transfected cells confirmed impaired SCF complex assembly and autophagic flux ([PMID:26753747]). FBXO32-knockout mice recapitulate DCM phenotypes, including ventricular dilation and contractile dysfunction. Transcriptomic and biochemical assays revealed dysregulated unfolded protein response with CHOP-mediated apoptosis in mutant hearts ([PMID:34272480]). These data concordantly implicate disruption of ubiquitin-proteasome and autophagy pathways in pathogenesis.

No studies to date have reported compelling evidence disputing the FBXO32–DCM link. Rare FBXO32 variants found in statin-myopathy cohorts lack segregation or functional validation and remain unconfirmed as DCM risk factors (PMID:27296017).

Integration of genetic segregation in multiple families with corroborating in vivo and in vitro functional assays fulfills criteria for a Strong ClinGen gene–disease association. Both genetic and experimental data converge on haploinsufficiency of FBXO32 leading to cardiomyocyte proteostasis failure and DCM.

Key Take-home: FBXO32 should be included in genetic testing panels for autosomal recessive dilated cardiomyopathy due to its strong clinical validity and mechanistic underpinning.

References

• Genome biology • 2016 • FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy. PMID:26753747
• BMC medical genetics • 2016 • A substitution mutation in cardiac ubiquitin ligase, FBXO32, is associated with an autosomal recessive form of dilated cardiomyopathy. PMID:26768247
• Communications biology • 2021 • Mutation in FBXO32 causes dilated cardiomyopathy through up-regulation of ER-stress mediated apoptosis. PMID:34272480

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