Gain-of-function mutation in TASK-4 channels and severe cardiac conduction disorder.
Bottom Line: The heterozygous change (c.262G>A) resulted in the p.Gly88Arg mutation in the first extracellular pore loop.We demonstrate that KCNK17 is strongly expressed in human Purkinje cells and that overexpression of G88R leads to a hyperpolarization and strong slowing of the upstroke velocity of spontaneously beating HL-1 cells.Moreover, WES supports a second hit-hypothesis in severe arrhythmia cases and identified KCNK17 as a novel arrhythmia gene.
Affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.Show MeSH
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Mentions: After sequencing the key genes (e.g., TRPM4, LMNA) for PCCD, we first identified in the SCN5A gene an unpublished, single nucleotide exchange in the essential donor splice site of intron 22 (c.3963+1G>A) (Fig 2A). The boundary between exon 22 and exon 23 is located in the intracellular linker between transmembrane segments S4 and S5 in domain 3 (DIII) of the Nav1.5 α-subunit (Fig 2A–C). In consequence, skipping of exon 22 is very likely, since a mutation affecting the same splice site (c.3963+2T>C, reported as IVS22+2T>C) was shown to cause exonic skipping and a complete loss of channel function (Schott et al, 1999).
Affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.