New KCNQ1 mutations leading to haploinsufficiency in a general population1Defective trafficking of a KvLQT1 mutant

Gouas, Laëtitia; Bellocq, Chloé; Berthet, Myriam; Potet, F; Demolombe, Sophie; Forhan, Anne; Lescasse, Rachel; Simon, Françoise; Balkau, Beverley; Denjoy, Isabelle; Hainque, Bernard; Baró, Isabelle; Guicheney, Pascale

doi:10.1016/j.cardiores.2004.02.011

Cited by 50 publications

(31 citation statements)

References 47 publications

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“…Fifty-percent decrease in normal KCNQ4 channels may lead to mild hearing impairment. Haploinsufficiency has been suggested to underlie the pathogenesis of both long QT syndrome and benign familial neonatal convulsions caused by KCNQ1 and KCNQ2 or KCNQ3 mutations, respectively (Gouas et al 2004;Rogawski 2000). In contrast, the dominant-negative effect due to missense mutations significantly interferes with the normal channel subunit.…”

Section: Discussionmentioning

confidence: 99%

A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype–phenotype correlation

et al. 2006

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Autosomal-dominant, nonsyndromic hearing impairment is clinically and genetically heterogeneous. We encountered a large Japanese pedigree in which nonsyndromic hearing loss was inherited in an autosomal-dominant fashion. A genome-wide linkage study indicated linkage to the DFNA2 locus on chromosome 1p34. Mutational analysis of KCNQ4 encoding a potassium channel revealed a novel one-base deletion in exon 1, c.211delC, which generated a profoundly truncated protein without transmembrane domains (p.Q71fsX138). Previously, six missense mutations and one 13-base deletion, c.211_223del, had been reported in KCNQ4. Patients with the KCNQ4 missense mutations had younger-onset and more profound hearing loss than patients with the 211_223del mutation. In our current study, 12 individuals with the c.211delC mutation manifested late-onset and pure high-frequency hearing loss. Our results support the genotype-phenotype correlation that the KCNQ4 deletions are associated with later-onset and milder hearing impairment than the missense mutations. The phenotypic difference may be caused by the difference in pathogenic mechanisms: haploinsufficiency in deletions and dominant-negative effect in missense mutations.

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Section: Discussionmentioning

confidence: 99%

A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype–phenotype correlation

et al. 2006

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“…9 Among the 100 KCNQ1 mutations reported so far, only a few have been linked to a dysfunction of KCNQ1 at the molecular level, including defective trafficking 26 and a dominantnegative effect. 27 This study describes a novel molecular mechanism leading to the long QT syndrome and identifies its nature (electrostatic), the partner (a phospholipid), and the functional consequence of the altered interaction (a decrease in the channel open state).…”

Section: Discussionmentioning

confidence: 99%

Impaired KCNQ1–KCNE1 and Phosphatidylinositol-4,5-Bisphosphate Interaction Underlies the Long QT Syndrome

Park

Piron

Dahimène

et al. 2005

Circulation Research

103

121

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Abstract-Nearly a hundred different KCNQ1 mutations have been reported as leading to the cardiac long QT syndrome, characterized by prolonged QT interval, syncopes, and sudden death. We have previously shown that phosphatidylinositol-4,5-bisphosphate (PIP 2 ) regulates the KCNQ1-KCNE1 complex. In the present study, we show that PIP 2 affinity is reduced in three KCNQ1 mutant channels (R243H, R539W, and R555C) associated with the long QT syndrome. In giant excised patches, direct application of PIP 2 on the cytoplasmic face of the three mutant channels counterbalances the loss of function. Reintroduction of a positive charge by application of methanethiosulfonate ethylammonium on the cytoplasmic face of R555C mutant channels also restores channel activity. The channel affinity for a soluble analog of PIP 2 is decreased in the three mutant channels. By using a model that describes the KCNQ1-KCNE1 channel behavior and by fitting the relationship between the kinetics of deactivation and the current amplitude obtained in whole-cell experiments, we estimated the PIP 2 binding and dissociation rates on wild-type and mutant channels. The dissociation rate of the three mutants was higher than for the wild-type channel, suggesting a decreased affinity for PIP 2 . PIP 2 binding was magnesium-dependent, and the PIP 2 -dependent equilibrium constant in the absence of magnesium was higher with the wild-type than with the mutant channels. Altogether, our data suggest that a reduced PIP 2 affinity of KCNQ1 mutants can lead to the long QT syndrome. Key Words: KCNQ1 Ⅲ KCNE1 Ⅲ phosphatidylinositol-4,5-bisphosphate Ⅲ long QT syndrome K CNQ1 is the pore-forming subunit of the channel complex (composed of KCNQ1 and its regulator KCNE1) underlying the delayed rectifier potassium current I Ks , a key modulator of the action potential duration in the human heart. 1,2 Nearly 100 KCNQ1 mutations have been reported to cause the long QT syndrome, a genetic disease characterized by prolonged cardiac repolarization, cardiac arrhythmias, and a high risk of sudden death. 3,4 Phosphaditylinositol-4,5-bisphosphate (PIP 2 ) is an important intracellular regulator of many ion channels and transporters. [5][6][7][8] We showed recently that intracellular PIP 2 regulates KCNQ1-KCNE1 channel activity in such a way that PIP 2 stabilizes the open state of the channels, leading to an increased current amplitude, slowed deactivation kinetics, and a shift in the activation curve toward negative potentials. 9 In general, it is known that positively charged amino acids are implicated in channel-PIP 2 interactions. 10 -13 Because various KCNQ1 mutations producing neutralization of a residue in an intracellular segment of the channel protein lead to reduced current amplitude, accelerated deactivation, and shift in the activation curve toward positive potentials, 14,15 we hypothesized that mutations neutralizing a positive charge (eg, R243H, R539W, and R555C) may act through an impaired channel-PIP 2 interaction. We thus compared the effects of PIP 2 on wild-typ...

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“…Functional studies of mutated Kv7.1 indicate multiple biophysical consequences as a result of altering the function of I Ks . Functional investigation of KCNQ1 mutations have shown them to result in defective trafficking [Gouas et al, 2004] and dominant-negative (loss-of-function) effects . Moreover, several mutations have been reported to affect binding of interacting proteins.…”

Section: Mutations In Kcnq1 (Lqt1 and Sqt2)mentioning

confidence: 99%

The genetic basis of long QT and short QT syndromes: A mutation update

et al. 2009

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Long QT and short QT syndromes (LQTS and SQTS) are cardiac repolarization abnormalities that are characterized by length perturbations of the QT interval as measured on electrocardiogram (ECG). Prolonged QT interval and a propensity for ventricular tachycardia of the torsades de pointes (TdP) type are characteristic of LQTS, while SQTS is characterized by shortened QT interval with tall peaked T-waves and a propensity for atrial fibrillation. Both syndromes represent a high risk for syncope and sudden death. LQTS exists as a congenital genetic disease (cLQTS) with more than 700 mutations described in 12 genes (LQT1-12), but can also be acquired (aLQTS). The genetic forms of LQTS include Romano-Ward syndrome (RWS), which is characterized by isolated LQTS and an autosomal dominant pattern of inheritance, and syndromes with LQTS in association with other conditions. The latter includes Jervell and Lange-Nielsen syndrome (JLNS), Andersen syndrome (AS), and Timothy syndrome (TS). The genetics are further complicated by the occurrence of double and triple heterozygotes in LQTS and a considerable number of nonpathogenic rare polymorphisms in the involved genes. SQTS is a very rare condition, caused by mutations in five genes (SQTS1-5). The present mutation update is a comprehensive description of all known LQTS-and SQTS-associated mutations.

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New KCNQ1 mutations leading to haploinsufficiency in a general population1Defective trafficking of a KvLQT1 mutant

Cited by 50 publications

References 47 publications

A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype–phenotype correlation

A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype–phenotype correlation

Impaired KCNQ1–KCNE1 and Phosphatidylinositol-4,5-Bisphosphate Interaction Underlies the Long QT Syndrome

The genetic basis of long QT and short QT syndromes: A mutation update

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