A Kir3.4 mutation causes Andersen–Tawil syndrome by an inhibitory effect on Kir2.1

Abstract

We propose that KCNJ5 is a second gene causing Andersen-Tawil syndrome. The inhibitory effects of mutant Kir3.4 on inwardly rectifying potassium channels may account for the clinical presentation in both skeletal and heart muscles.

Child Neurology: Andersen-Tawil syndrome

“…4 Recently, a mutation in KCJN5, which encodes the Kir3.4 subunit, has been linked to ATS and is thought to exert an inhibitory effect on the inward rectifier potassium current. 5 In ATS, episodes of periodic paralysis first develop during childhood or adolescence and typically last between several hours and several days. Serum potassium levels during the episodes may be normal, elevated, or reduced.…”

The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels

“…Interestingly, association of GIRK with IRK1 has been proposed (Ishihara, Yamamoto, & Kubo, 2009;Kokunai et al, 2014). If functional IRK1/GIRK4 channels exist and GIRK4 may regulate IRK1's current, our understanding of cardiac K + conductances and some pathologies will require considerable revision.…”

“…If functional IRK1/GIRK4 channels exist and GIRK4 may regulate IRK1's current, our understanding of cardiac K + conductances and some pathologies will require considerable revision. GIRK4-IRK1 hypothesis could explain both cardiac and skeletal muscle Andersen-Tawil syndrome-like symptoms caused by a G378R mutation of GIRK4 (Kokunai et al, 2014); Andersen-Tawil syndrome is a known channelopathy of IRK1 (Donaldson, Yoon, Fu, & Ptacek, 2004;Tristani-Firouzi & Etheridge, 2010). The underlying mechanism has been proposed to involve a reduction in I basal of IRK1/GIRK4 G387R heterotetramers compared to wild-type IRK1/GIRK4 channels (Kokunai et al, 2014).…”

“…GIRK4-IRK1 hypothesis could explain both cardiac and skeletal muscle Andersen-Tawil syndrome-like symptoms caused by a G378R mutation of GIRK4 (Kokunai et al, 2014); Andersen-Tawil syndrome is a known channelopathy of IRK1 (Donaldson, Yoon, Fu, & Ptacek, 2004;Tristani-Firouzi & Etheridge, 2010). The underlying mechanism has been proposed to involve a reduction in I basal of IRK1/GIRK4 G387R heterotetramers compared to wild-type IRK1/GIRK4 channels (Kokunai et al, 2014). However, coexpression of GIRK4 with IRK1 does not increase IRK1 currents nor yield any Gβγ-sensitive currents (Ishihara et al, 2009) and it is possible that GIRK4 regulates IRK1 biogenesis rather than producing functional heterotetramers.…”

Andersen-Tawil syndrome: Clinical presentation and predictors of symptomatic arrhythmias – Possible role of polymorphisms K897T in KCNH2 and H558R in SCN5A gene

“…Recent research showed that KCNJ5 , encoding the G-protein-activated inwardly rectifying potassium channel 4 (Kir3.4), could be a second gene causing Andersen-Tawil syndrome. The inhibitory effects of mutant Kir3.4 on Kir2.1 channel may cause the clinical presentation in both skeletal and heart muscles [5]. …”