PubMed 21836131

Referenced in Channelpedia wiki pages of: Kir6.1

Automatically matched channels: none

Title: Loss-of-Function Mutations in the KCNJ8-Encoded Kir6.1 KATP Channel and Sudden Infant Death Syndrome.

Authors: David J Tester, Bi-Hua Tan, Argelia Medeiros-Domingo, Chunhua Song, Jonathan C Makielski, Michael J Ackerman

Journal, date & volume: , 2011 Aug 11 , ,

PubMed link:


BACKGROUND: -Approximately 10% of sudden infant death syndrome (SIDS) may stem from cardiac channelopathies. The KCNJ8-encoded Kir6.1 (K(ATP)) channel critically regulates vascular tone and cardiac adaptive response to systemic metabolic stressors, including sepsis. KCNJ8-deficient mice are prone to premature sudden death, particularly with infection. We determined the spectrum, prevalence, and function of KCNJ8 mutations in a large SIDS cohort. METHODS AND RESULTS: -Using PCR, DHPLC, and DNA sequencing, comprehensive open reading frame/splice-site mutational analysis of KCNJ8 was performed on genomic DNA isolated from necropsy tissue on 292 unrelated SIDS cases (178 males, 204 white, age 2.9 ± 1.9 months). KCNJ8 mutations were co-expressed heterologously with SUR2A in COS-1 cells and characterized using whole cell patch-clamp. Two novel KCNJ8 mutations were identified. A 5-month-old white male had an in-frame deletion (E332del) and a 2-month-old black female had a missense mutation (V346I). Both mutations localized to Kir6.1's C-terminus, involved conserved residues, and were absent in 400 and 200 ethnic-matched reference alleles respectively. Both cases were negative for mutations in established channelopathic genes. Compared to WT, the pinacidil-activated K(ATP) current was decreased 45% to 68% for Kir6.1-E322del and 40% to 57% for V346I between -20 mV to 40 mV. CONCLUSIONS: -Molecular and functional evidence implicated loss-of-function KCNJ8 mutations as a novel pathogenic mechanism in SIDS, possibly by predisposition of a maladaptive cardiac response to systemic metabolic stressors akin to the mouse models of KCNJ8 deficiency.