| A common single nucleotide polymorphism can exacerbate long-QT type 2 syndrome leading to sudden infant death. | |
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MedLine Citation:
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PMID: 20181576 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine. We present a family in which a common polymorphism (single nucleotide polymorphism) inherited from the father, combined with a stop codon mutation inherited from the mother (both asymptomatic), led to 2 cases of sudden infant death. METHODS AND RESULTS: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, CACNA1c, CACNB2b, and KCNJ2 genes were amplified and analyzed by direct sequencing. Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary (CHO-K1) and COS-1 cells. An asymptomatic woman presenting after the death of her 2-day-old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis. The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc (560 ms). The mother was asymptomatic but displayed a prolonged QTc. Genetic screening of the mother revealed a heterozygous nonsense mutation (P926AfsX14) in KCNH2, predicting a stop codon. The father was asymptomatic with a normal QTc but had a heterozygous polymorphism (K897T) in KCNH2. The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14. Heterologous coexpression of K897T and P926AfsX14 led to loss of function of HERG current much greater than expression of K897T or P926AfsX14 alone. CONCLUSIONS: Our data suggest that a common polymorphism (K897T) can markedly accentuate the loss of function of mildly defective HERG channels, leading to long-QT syndrome-mediated arrhythmias and sudden infant death. |
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Authors:
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Eyal Nof; Jonathan M Cordeiro; Guillermo J Pérez; Fabiana S Scornik; Kirstine Calloe; Barry Love; Elena Burashnikov; Gabriel Caceres; Moshe Gunsburg; Charles Antzelevitch |
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Publication Detail:
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Type: Case Reports; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-02-24 |
Journal Detail:
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Title: Circulation. Cardiovascular genetics Volume: 3 ISSN: 1942-3268 ISO Abbreviation: Circ Cardiovasc Genet Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-21 Completed Date: 2010-07-27 Revised Date: 2011-10-20 |
Medline Journal Info:
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Nlm Unique ID: 101489144 Medline TA: Circ Cardiovasc Genet Country: United States |
Other Details:
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Languages: eng Pagination: 199-206 Citation Subset: IM |
Affiliation:
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Masonic Medical Research Laboratory, Utica, NY 13501, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals CHO Cells Codon, Nonsense Cricetinae Cricetulus Death, Sudden, Cardiac / etiology* Electrophysiology Ether-A-Go-Go Potassium Channels / genetics, metabolism Female Genetic Counseling Heterozygote Humans Infant Long QT Syndrome / genetics* Pedigree Polymorphism, Single Nucleotide* Pregnancy Young Adult |
| Grant Support | |
ID/Acronym/Agency:
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HL47678/HL/NHLBI NIH HHS; R01 HL047678-16/HL/NHLBI NIH HHS; R01 HL047678-18/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Codon, Nonsense; 0/ERG1 potassium channel; 0/Ether-A-Go-Go Potassium Channels |
| Comments/Corrections | |
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