DPP6 – Paroxysmal Familial Ventricular Fibrillation

Paroxysmal familial ventricular fibrillation (VF) is an inherited cardiac arrhythmia characterized by recurrent sudden cardiac arrest in structurally normal hearts. DPP6 encodes an auxiliary subunit of the transient outward potassium current (I_to) channel complex, and multiple lines of evidence implicate heterozygous DPP6 variants and a noncoding risk haplotype in predisposition to this disorder [PMID:19285295]. Genetic linkage and haplotype‐sharing analysis in three distantly related families identified a conserved segment on chromosome 7q36 encompassing DPP6, which was also shared by 7 of 42 independent IVF patients ([PMID:19285295]). Quantitative mRNA analysis demonstrated a 20‐fold increase in DPP6 transcript levels in myocardium of risk-haplotype carriers compared to controls, implicating overexpression as a likely pathogenic mechanism ([PMID:19285295]).

Subsequent sequencing in a Chinese pedigree with sudden cardiac death and syncope revealed a novel missense variant, c.1578G>C (p.Gln526His), which co-segregated with affected individuals and was absent from unaffected relatives and population controls ([PMID:29474731]). Patch-clamp studies in HEK293 cells demonstrated that p.Gln526His confers a gain of function with increased I_to current density and altered activation/inactivation kinetics, consistent with a hyperexcitable phenotype ([PMID:29474731]). In a Dutch idiopathic VF registry of 419 patients, DPP6 genetic testing (including the risk haplotype) identified LP/P variants in 15% of cases, with 39 carriers of the risk haplotype (70% of LP/P) and additional arrhythmia gene variants in others; broad NGS panels without the haplotype yield only 3% positive findings, underscoring DPP6’s diagnostic importance ([PMID:37967257]).

Functional studies in patient-derived cardiomyocytes further confirmed that DPP6 variants increase I_to and prolong action potential duration; CRISPR/Cas9 correction of the c.2561T>C (p.Leu854Pro) mutation normalized I_to currents in iPSC-derived cardiomyocytes, validating the gain-of-function mechanism ([PMID:38272106]). No coding DPP6 mutations were detected in 32 of 33 IVF index cases screened by extended NGS panels, supporting locus specificity ([PMID:28087426]). Collectively, these data define a definitive association between heterozygous DPP6 gain-of-function variants or regulatory haplotypes and paroxysmal familial VF.

References

• American Journal of Human Genetics • 2009 • Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation PMID:19285295
• QJM • 2018 • A novel mutation of dipeptidyl aminopeptidase-like protein-6 in a family with suspicious idiopathic ventricular fibrillation PMID:29474731
• Heart Rhythm • 2023 • Next-generation sequencing panels in idiopathic ventricular fibrillation: yield of DPP6 risk alleles PMID:37967257
• Experimental Cell Research • 2024 • Correction of Ito in human induced pluripotent stem cell-derived cardiomyocyte carrying DPP6 mutation in early repolarization syndrome by CRISPR/Cas9 genome editing PMID:38272106

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