Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome.

Autor: Faridi R; Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA.; National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan., Tona R; Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA., Brofferio A; Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health Clinical Center, Bethesda, Maryland, USA., Hoa M; Auditory Development and Restoration Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA., Olszewski R; Auditory Development and Restoration Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA., Schrauwen I; Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Assir MZK; Allama Iqbal Medical Research Centre, Jinnah Hospital Complex, Lahore, Pakistan., Bandesha AA; Cardiology Department, The Pakistan Institute of Medical Sciences, Islamabad, Pakistan., Khan AA; National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan., Rehman AU; Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA., Brewer C; Audiology Unit, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, Maryland, USA., Ahmed W; Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan., Leal SM; Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Riazuddin S; Allama Iqbal Medical Research Centre, Jinnah Hospital Complex, Lahore, Pakistan., Boyden SE; Section on Genetics of Communication Disorders, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA., Friedman TB; Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2019 Feb; Vol. 40 (2), pp. 162-176. Date of Electronic Publication: 2018 Dec 12.
DOI: 10.1002/humu.23689
Abstrakt: KCNE1 encodes a regulatory subunit of the KCNQ1 potassium channel-complex. Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization. Recessive variants in these genes are associated with Jervell and Lange-Nielson syndrome (JLNS1 and JLNS2), a cardio-auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death. Some normal-hearing carriers of heterozygous missense variants of KCNE1 and KCNQ1 have prolonged QT intervals, a dominantly inherited phenotype designated Romano-Ward syndrome (RWS), which is also associated with arrhythmias and elevated risk of sudden death. Coassembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism. This paper reviews variants of KCNE1 and their associated phenotypes, including biallelic truncating null variants of KCNE1 that have not been previously reported. We describe three homozygous nonsense mutations of KCNE1 segregating in families ascertained ostensibly for nonsyndromic deafness: c.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). Some individuals carrying missense variants of KCNE1 have RWS. However, heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2, indicating a complex genotype-phenotype spectrum for KCNE1 variants.
(© 2018 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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