IsK and KvLQT1: Mutation in Either of the Two Subunits of the Slow Component of the Delayed Rectifier Potassium Channel Can Cause Jervell and Lange-Nielsen Syndrome

Tyson, Jess; Tranebjærg, Lisbeth; Bellman, Susan; Wren, Christopher; Taylor, J F; Bathen, Jørn; Aslaksen, Bjørn; Sørland, Svein; Lund, Ole; Malcolm, Sue; Pembrey, Marcus; Bhattacharya, Siladitya; Bitner‐Glindzicz, Maria

doi:10.1093/hmg/6.12.2179

Cited by 284 publications

(170 citation statements)

References 26 publications

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“…En 1994 et 1995, trois autres localisations ont été publiées, sur les chromosomes 7 en 7q35-36 (LQT2), 3 en 3p21-24 (LQT3) [8], et 4 en 4q25-27 (LQT4) [9]. Un cinquième locus en 21q22 a été identifié en 1997 par une approche « gène candidat » (LQT5) [10][11][12]. Quatre gènes ont été identifiés jusqu'à présent, ils codent tous pour des sous-unités de canaux sodiques molécule, et également de mutations aboutissant à des protéines tronquées.…”

Section: Bases Moléculaires Des Arythmies Héréditairesunclassified

“…Comme nous le verrons plus loin, KvLQT1, associé à une petite protéine membranaire IsK (encore appelée minK et codée par le gène KCNE1), est responsable du courant IKs (figure 1) [28,30]. [11,31,32]. Il s'ensuit que, pour identifier ces mutations, la séquence complète du gène KVLQT1 doit être analysée.…”

Section: Kvlqt1unclassified

“…Il s'ensuit que, pour identifier ces mutations, la séquence complète du gène KVLQT1 doit être analysée. Pour KCNE1, dont la séquence ne compte que 387 bases regroupées en un seul exon, l'analyse directe du gène est facile et a conduit à l'identification de quatre mutations, une mutation faux-sens dans le domaine amino-terminal extracellulaire [10], une mutation complexe aboutissant au changement de deux acides aminés dans le domaine transmembranaire [11] et deux mutations faux-sens dans la partie cytoplasmique carboxy-terminale [10,12].…”

Section: Kvlqt1unclassified

“…En revanche, en l'absence totale de fonction du canal, comme c'est le cas chez les individus homozygotes, le défaut cardiaque est très sévère et la surdité congénitale est la consé-quence de la perte de fonction du canal dans l'oreille. Les deux autres mutations JLN identifiées sont une insertion d'un nucléotide [32] et une délétion de 5 pb dans la boucle S2-S3 [11] qui entraînent toutes deux un décalage de la phase de lecture et aboutissent à des protéines anormales et tronquées. De telles protéines n'ont que très peu de chances d'être capables de s'assembler, et donc d'avoir un effet dominant néga-tif important.…”

Section: Les Canaux Peuvent Se Trouver Dans 3 Conformations De Baseunclassified

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Bases moléculaires des arythmies héréditaires.

Guicheney¹,

Barhanin²,

Marec³

1998

Med Sci (Paris)

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Section: Bases Moléculaires Des Arythmies Héréditairesunclassified

Section: Kvlqt1unclassified

Section: Les Canaux Peuvent Se Trouver Dans 3 Conformations De Baseunclassified

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Bases moléculaires des arythmies héréditaires.

Guicheney¹,

Barhanin²,

Marec³

1998

Med Sci (Paris)

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“…Indeed, evidence for the presence of deafness-associated K + channel proteins, KCNQ1 (or KVLQT1) [10], KCNQ4 [8] and IsK [15], has been presented. In man, mutations in either KCNQ1 or ISK cause Jervell and Lange-Lielsen syndrome [14], and those in KCNQ4 are associated with non-syndromic DFNA2 [8]. Mutations in gap junction proteins, GJB2 [7], GJB3 [16] and GJB6 [4], which are implicated in intercellular difusion of K + ions, are also the causes of inner ear impairments in human.…”

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A New Mouse Model with Cochleo-Saccular Type Inner Ear Defects.

et al. 2001

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Abstract:We found a new inner ear mutant exhibiting abnormal behavior, such as circling and head shaking, in a breeding stock of SJL/J mice. The traits are inherited in a simple autosomal-recessive fashion. Animals homozygous for the responsible gene, designated cosa, show no startle response to sounds and an inability to swim. In the inner ears of cosa/cosa homozygous, but not +/cosa heterozygous adults, histopathological features of severe damage that are typical for 'cochleo-saccular' or 'spotting' mutants have been demonstrated. We suggest here that the abnormal mice carry a mutation of a gene that is developmentally switched on in the early stages of development and is involved in endolymph homeostasis. Key words: deafness, mutant mouse, vestibular dysfunction One in every 1,000-2,000 children born is afflicted with hereditary deafness. To date, over 30 different genes that affect the inner ear function have been identified in man [6], while mutations of over 70 different genes are reported to be associated with inner ear impairments in mice [9]. Animal models have considerably contributed to the identification of responsible genes in human deafness [3,11], and in this respect, the necessity and importance of establishing new mutant models of experimental animals should be emphasized. Equally to be emphasized is that the analysis of different alleles could give valuable information about genotype-phenotype correlations. We describe here on a new mouse model which has 'cochleo-saccular type' inner ear defects. In a breeding stock of SJL/J mice, a few animals that were hyperactive and displayed head shaking and circling behavior were found. The animals abnormal in behavior were isolated and bred by full-sib matings, and they have now been maintained for up to eight generations in the Laboratory of Animal Management & Resources, Graduate School of Bioagricultural Sciences, Nagoya University. No differences are found in appearance between abnormal and normal SJL mice. To characterize further behavioral abnormalities, the animals were subjected to swimming tests, air-righting reflex tests and head nystagmus reflex tests by essentially the same methods as those employed for characterizing BUS/Idr mice [5]. The result was that they gave no positive results in any of these tests. In

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Jervell and Lange-Nielsen syndrome: A Norwegian perspective

Tranebjærg

Bathen²,

Tyson³

et al. 1999

Am. J. Med. Genet.

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Jervell and Lange-Nielsen syndrome (MIM 220400; JLNS), is a rare form of profound congenital deafness combined with syncopal attacks and sudden death due to prolonged QTc; it is an autosomal recessive trait. After its first description in Norway in 1957, later reports from many other countries have confirmed its occurrence. Nowhere is the prevalence so high as in Norway, where we estimate a prevalence of at least 1:200,000. The KCNQ1 and KCNE1 proteins coassemble in a potassium channel, and mutations in either the KCNQ1 gene or the KCNE1 gene disrupt endolymph production in the stria vascularis in the cochlea, causing deafness. KCNQ1 seems to be the major gene in JLNS. Long QT syndrome (LQTS) is a separate disorder of either autosomal dominant or recessive inheritance caused by mutations in four different ion channel genes; KCNQ1 is the one most frequently involved. Some heterozygous carriers of JLNS mutations in either gene may suffer from prolonged QTc and be symptomatic LQTS patients with a need for appropriate medical treatment to prevent life-threatening cardiac arrhythmia. In general, frameshift/stop mutations cause JLNS, and missense/splice site mutations cause LQTS, but a precise genotype-phenotype correlation in LQTS and JLNS is not established, which complicates both genetic counseling and clinical risk evaluation in carriers. We review JLNS from a Norwegian perspective because of the unusually high prevalence, the genetic homogeneity associated with considerable mutational heterogeneity, and some evidence for recurrent mutational events as well as one founder mutation. We outline the clinical implications for investigation of deaf children and cases of sudden infant death syndrome as well as careful electrocardiographic monitoring of identified mutation carriers to prevent sudden death. Am. J. Med. Genet. (Semin. Med. Genet.) 89:137-146, 1999.

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IsK and KvLQT1: Mutation in Either of the Two Subunits of the Slow Component of the Delayed Rectifier Potassium Channel Can Cause Jervell and Lange-Nielsen Syndrome

Cited by 284 publications

References 26 publications

Bases moléculaires des arythmies héréditaires.

Bases moléculaires des arythmies héréditaires.

A New Mouse Model with Cochleo-Saccular Type Inner Ear Defects.

Jervell and Lange-Nielsen syndrome: A Norwegian perspective

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