Identification of <i>KCNQ1</i> compound heterozygous mutations in three Chinese families with Jervell and Lange-Nielsen Syndrome

Wang, Cuicui; Lu, Yu; Cheng, Jing; Liu, Wei; Peng, Weihua; Zhang, Di; Duan, Hong; Han, Dongyi; Yuan, Huijun

doi:10.1080/00016489.2016.1260156

Cited by 6 publications

(8 citation statements)

References 18 publications

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“…In general, a dominant-negative inhibitory effect is suspected for dominantly inherited missense Kv7 variants that retain the C-terminal tetramerization region. For example, for Kv7.4 missense variants, a dominant-negative inhibitory effect has been demonstrated for p.L47P, p.N264S, p.S269F, p.S273A, p.L274H, p.W276S, p.T278A, p.L281M, p.L281S, p.G285C, p.G285S, p.L295P, p.G296S, p.G321S, and p.R433W [ 52 , 54 , 58 , 68 , 73 , 74 , 76 ]. However, these studies would not rule out the possibility that some missense variants are also cytotoxic.…”

Section: Remaining Questions and Future Directionsmentioning

confidence: 99%

“…Not a Kv7.4 variant, but the expression of a missense Kv7.2 variant, Kv7.2 M518V , was reported to induce neuronal death [ 123 ]. Missense mutations that were reported to impair cell membrane targeting of Kv7.4, i.e., p.L274H, p.W276S, p.L281S, p.G285C, p.G285S, p.G296S, and p.G321S [ 58 , 68 , 81 ], are of particular interest because impaired cell membrane targeting implies a structural defect in a mutated protein, an intracellular accumulation of which could induce cellular stress. It should be pointed out that many previous studies reporting a dominant-negative inhibitory effect for Kv7 variants used transiently transfected cells.…”

Section: Remaining Questions and Future Directionsmentioning

confidence: 99%

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The Pathological Mechanisms of Hearing Loss Caused by KCNQ1 and KCNQ4 Variants

Homma

2022

Biomedicines

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Deafness-associated genes KCNQ1 (also associated with heart diseases) and KCNQ4 (only associated with hearing loss) encode the homotetrameric voltage-gated potassium ion channels Kv7.1 and Kv7.4, respectively. To date, over 700 KCNQ1 and over 70 KCNQ4 variants have been identified in patients. The vast majority of these variants are inherited dominantly, and their pathogenicity is often explained by dominant-negative inhibition or haploinsufficiency. Our recent study unexpectedly identified cell-death-inducing cytotoxicity in several Kv7.1 and Kv7.4 variants. Elucidation of this cytotoxicity mechanism and identification of its modifiers (drugs) have great potential for aiding the development of a novel pharmacological strategy against many pathogenic KCNQ variants. The purpose of this review is to disseminate this emerging pathological role of Kv7 variants and to underscore the importance of experimentally characterizing disease-associated variants.

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Section: Remaining Questions and Future Directionsmentioning

confidence: 99%

Section: Remaining Questions and Future Directionsmentioning

confidence: 99%

The Pathological Mechanisms of Hearing Loss Caused by KCNQ1 and KCNQ4 Variants

Homma

2022

Biomedicines

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“…Prior to MPS, screening on common variants in GJB2 , SLC26A4, or MT‐RNR1 was conducted and no causative variants were detected in the three participants. Massively parallel sequencing covering 110 NSHL associated genes was then completed in the subjects using Agilent SureSelect Target Enrichment Kit (Agilent Technologies, Santa Clara, CA) and Illumina HiSeq 2000 System (Illumina, San Diego, CA) as described (Wang et al, ).…”

Section: Methodsmentioning

confidence: 99%

Identification of a complex genomic rearrangement in TMPRSS3 by massively parallel sequencing in Chinese cases with prelingual hearing loss

Tan

Wang

et al. 2019

Molec Gen & Gen Med

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Background Genetic variants in TMPRSS3 have been causally linked to autosomal recessive nonsyndromic hearing loss (HL) at the DFNB8 and DFNB10 loci. These variants include both single nucleotide and copy number variations (CNVs). In this study, we aim to identify the genetic cause in three Chinese subjects with prelingual profound sensorineural HL. Methods We applied targeted genomic enrichment and massively parallel sequencing to screen 110 genes associated with nonsyndromic HL in the three affected subjects. CNVplex® analysis and polymerase chain reaction (PCR) were performed for CNV detection. Results We identified biallelic variations in TMPRSS3 including a novel complex genomic rearrangement and a novel missense mutation, c.551T>C. We have mapped the breakpoints of the genomic rearrangement and showed that it consisted of two deletions and an inversion encompassing exon 3 to exon 9 of TMPRSS3. Conclusion Our study expanded the mutational spectrum of TMPRSS3 to include complex genomic rearrangements. It showcased the importance of an integrative approach to investigate CNVs and their contribution to HL.

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“…These reports do not provide unequivocal conclusions about the association of the variant with arrhythmic disorders. In addition, co-occurrence with another pathogenic variant has been reported ( KCNQ1 c.1484_1485delCT, p.L496AfsX19, [ 41 ]), providing supporting evidence for a benign role.…”

Section: Cases Presentationmentioning

confidence: 97%

“…An in vitro splice assay showed that this variant causes exon 4 skipping and premature protein truncation [ 32 ]. This variant was reported in the literature in individuals affected with LQTS and Jervell and Lange-Nielsen syndrome [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. These reports do not provide unequivocal conclusions about the association of the variant with arrhythmic disorders.…”

Section: Cases Presentationmentioning

confidence: 99%

Eosinophilic Infiltration of the Sino-Atrial Node in Sudden Cardiac Death Caused by Long QT Syndrome

Grassi

Campuzano

Coll

et al. 2022

IJMS

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Sudden death is defined as the unexpected death of a healthy person that occurs within the first hour of the onset of symptoms or within 24 h of the victim being last seen alive. In some of these cases, rare deleterious variants of genes associated with inherited cardiac disorders can provide a highly probable explanation for the fatal event. We report the case of a 21-year-old obese woman who lost consciousness suddenly in a public place and was pronounced dead after hospital admission. Clinical autopsy showed an inconclusive gross examination, while in the histopathological analysis an eosinophilic inflammatory focus and interstitial fibrosis in the sino-atrial node were found. Molecular autopsy revealed an intronic variant in the KCNQ1 gene (c.683 + 5G > A), classified as likely pathogenic for long QT syndrome according to the guidelines provided by the American College of Medical Genetics and Genomics. Therefore, there were many anomalies that could have played a role in the causation of the sudden death, such as the extreme obesity, the cardiac anomalies and the KNCQ1 variant. This case depicts the difficult interpretation of rare cardiac structural abnormalities in subjects carrying rare variants responsible for inherited arrhythmic disorders and the challenge for the forensic pathologist to make causal inferences in the determinism of the unexpected decease.

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Identification of KCNQ1 compound heterozygous mutations in three Chinese families with Jervell and Lange-Nielsen Syndrome

Cited by 6 publications

References 18 publications

The Pathological Mechanisms of Hearing Loss Caused by KCNQ1 and KCNQ4 Variants

The Pathological Mechanisms of Hearing Loss Caused by KCNQ1 and KCNQ4 Variants

Identification of a complex genomic rearrangement in TMPRSS3 by massively parallel sequencing in Chinese cases with prelingual hearing loss

Eosinophilic Infiltration of the Sino-Atrial Node in Sudden Cardiac Death Caused by Long QT Syndrome

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