Tester, David J.; Tan, Bi-Hua; Medeiros Domingo, Argelia; Song, Chunhua; Makielski, Jonathan C.; Ackerman, Michael J. (2011). Loss-of-function mutations in the KCNJ8-encoded Kir6.1 K(ATP) channel and sudden infant death syndrome. Circulation - cardiovascular genetics, 4(5), pp. 510-515. Lippincott Williams & Wilkins 10.1161/CIRCGENETICS.111.960195
Full text not available from this repository. (Request a copy)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 polymerase chain reaction, denaturing high-performance liquid chromatography, 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 coexpressed 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 with WT, the pinacidil-activated K(ATP) current was decreased 45% to 68% for Kir6.1-E332del and 40% to 57% for V346I between -20 mV and 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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology |
UniBE Contributor: |
Medeiros Domingo, Argelia |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1942-325X |
Publisher: |
Lippincott Williams & Wilkins |
Language: |
English |
Submitter: |
Argelia Medeiros Domingo |
Date Deposited: |
20 Jun 2014 11:11 |
Last Modified: |
05 Dec 2022 14:28 |
Publisher DOI: |
10.1161/CIRCGENETICS.111.960195 |
PubMed ID: |
21836131 |
URI: |
https://boris.unibe.ch/id/eprint/42272 |
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