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

Kamada, Fumiaki; Kure, Shigeo; Kawamata, Takayuki; Suzuki, Yôichi; Oshima, Takeshi; Ichinohe, Akiko; Kojima, Kanako; Niihori, Tetsuya; Kanno, Junko; Narumi, Yoko; Narisawa, Ayumi; Kato, Kumi; Aoki, Yoko; Ikeda, Katsuhisa; Kobayashi, Toshimitsu; Matsubara, Yoichi

doi:10.1007/s10038-006-0384-7

Cited by 50 publications

(55 citation statements)

References 21 publications

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“…In comparison, renal involvement was found in only two other patients, one with a suspected splicing mutation (c. 1261 þ 5G > A, Patient 13), and one with a frameshift mutation in exon 14 (c.1397dupT, Patient 14). These findings suggest that certain EYA1 proteins retaining partial function may have dominant-negative activity and produce distinct phenotypic consequences as reported in other dominant conditions [Inoue et al, 2004;Boyer et al, 2005;Kamada et al, 2006].…”

Section: Discussionmentioning

confidence: 83%

A recurrent EYA1 mutation causing alternative RNA splicing in branchio‐oto‐renal syndrome: Implications for molecular diagnostics and disease mechanism

Stockley

Mendoza‐Londono

Propst

et al. 2009

American J of Med Genetics Pt A

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Branchio-oto-renal syndrome is a heterogeneous disorder inherited in an autosomal dominant pattern, characterized by branchial arch abnormalities, hearing loss and renal abnormalities, with mutations in EYA1 reported in 30-70% of patients. We have applied a molecular testing strategy of sequencing of the complete coding region/flanking intronic regions and multiple ligation probe amplification analysis of EYA1 to a pediatric branchio-oto-renal proband cohort. EYA1 mutations were identified in 82% (14/17) of the probands. We also describe a novel recurrent EYA1 mutation c.867 + 5G > A found in five unrelated affected patients. RNA analysis showed that c.867 + 5G > A affects EYA1 splicing, producing an aberrant mRNA transcript lacking exon 8 and resulting in premature termination in exon 9. The aberrant transcript was present at approximately 50% level of wild-type EYA1 mRNA in fibroblasts, and is predicted to encode an EYA1 protein retaining the amino terminal transcriptional coactivator region but lacking the conserved carboxy terminal Eya phosphatase domain. Patients with the c.867 + 5G > A mutation were found to have more severe renal abnormalities than probands with other mutations in this cohort. Analysis of the c.867 + 5G > A mutation suggests that certain transcripts of EYA1 escape nonsense-mediated decay and encode truncated EYA proteins that may be capable of dominant-negative interactions producing distinct phenotypic features within the branchio-oto-renal spectrum.

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Section: Discussionmentioning

confidence: 83%

A recurrent EYA1 mutation causing alternative RNA splicing in branchio‐oto‐renal syndrome: Implications for molecular diagnostics and disease mechanism

Stockley

Mendoza‐Londono

Propst

et al. 2009

American J of Med Genetics Pt A

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“…15 To date, 16 mutations in KCNQ4 are associated with ADSNHL, including 11 missense, 11,12,15-24 1 nonsense, 15 1 splice-site mutation 21 and 3 deletions. 17,19,20 Of the 11 missense mutations reported, 6 are found in the P-loop and cause early-onset allfrequency hearing loss.…”

Section: Discussionmentioning

confidence: 99%

“…17 The second KCNQ4 deletion, c.211delC, was found in a Japanese family and is predicted to generate a truncated protein before the first transmembrane domain. 20 Generally, missense mutations in KCNQ4 have been associated with more severe, earlier-onset, all-frequency SNHL, while deletions are reported to cause a milder phenotype characterized by a later age of onset affecting only high frequencies. 12,15,19,20,22 Recently, a third deletion, c.664del18, reported in a Korean family causes the deletion of six amino acids in the intra-membrane loop between the fourth and fifth (S4 and S5) transmembrane domains.…”

Section: Discussionmentioning

confidence: 99%

“…20 Generally, missense mutations in KCNQ4 have been associated with more severe, earlier-onset, all-frequency SNHL, while deletions are reported to cause a milder phenotype characterized by a later age of onset affecting only high frequencies. 12,15,19,20,22 Recently, a third deletion, c.664del18, reported in a Korean family causes the deletion of six amino acids in the intra-membrane loop between the fourth and fifth (S4 and S5) transmembrane domains. 19 Baek et al (2010) verified the importance of the S4-S5 loop for proper potassium channel function.…”

Section: Discussionmentioning

confidence: 99%

“…Carriers of the p.S269del mutation also show that severity of the loss increases with age across all frequencies. 12,15,19,20,22,25 All family members heterozygous for the p.S269del mutation were diagnosed with SNHL, indicating that this KCNQ4 mutation is highly penetrant. However, three first-degree relatives of the index case did not inherit the KCNQ4 deletion or the deafness-associated DFNA2 haplotype but inherited the normal chromosome from the parent.…”

Section: Identification Of Phenocopiesmentioning

confidence: 99%

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Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL

et al. 2013

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Autosomal dominant sensorineural hearing loss (ADSNHL) is extremely genetically heterogeneous, making it difficult to molecularly diagnose. We identified a multiplex (n ¼ 28 affected) family from the genetic isolate of Newfoundland, Canada with variable SNHL and used a targeted sequencing approach based on population-specific alleles in WFS1, TMPRSS3 and PCDH15; recurrent mutations in GJB2 and GJB6; and frequently mutated exons of KCNQ4, COCH and TECTA. We identified a novel, in-frame deletion (c.806_808delCCT: p.S269del) in the voltage-gated potassium channel KCNQ4 (DFNA2), which in silico modeling predicts to disrupt multimerization of KCNQ4 subunits. Surprisingly, 10/23 deaf relatives are non-carriers of p.S269del. Further molecular characterization of the DFNA2 locus in deletion carriers ruled out the possibility of a pathogenic mutation other than p.S269del at the DFNA2A/B locus and linkage analysis showed significant linkage to DFNA2 (maximum LOD ¼ 3.3). Further support of genetic heterogeneity in family 2071 was revealed by comparisons of audio profiles between p.S269del carriers and non-carriers suggesting additional and as yet unknown etiologies. We discuss the serious implications that genetic heterogeneity, in this case observed within a single family, has on molecular diagnostics and genetic counseling.

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Deafness

Terrinoni¹,

Melino²,

Serra³

et al. 2009

Encyclopedia of Life Sciences

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Recent statistical data indicate that in western countries, at least 1:1000 suffer of congenital hearing impairment. Genetic factors are responsible for more than 60% of the congenital cases. Sometimes, however, hearing loss is a multifactorial disorder caused by both genetic and environmental factors. Molecular genetics of deafness has experienced remarkable progress in the last decade. Genes responsible for hereditary hearing impairment are being mapped and cloned progressively. This article, while reporting some syndromic conditions related to deafness, focuses on nonsyndromic hearing loss. Genes involved in this type of pathologic condition have only recently begun to be identified. Owing to genetic heterogeneity, private nature of most mutations and large size of most deafness genes, the molecular diagnostic possibilities in recessive deafness are today limited only for a few genes. Facility and benefits of genetic tracking, in particular, should make it an important public health issue so that determinations of early diagnosis of hearing loss can be properly established. Key concepts: Deafness is the most common sensory deficit in humans, affecting 1 in 1000 new‐born, and to date more than 23 different DFNB proteins have been discovered. DFNB proteins can be classified into two classes: (1) genes regulating potassium homeostasis and (2) genes producing proteins that are important in the formation of stereocilia. Owing to genetic heterogeneity, the molecular diagnostic possibilities in recessive deafness are still limited. However, facility and benefits of genetic tracking should make them an important public health issue.

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

Cited by 50 publications

References 21 publications

A recurrent EYA1 mutation causing alternative RNA splicing in branchio‐oto‐renal syndrome: Implications for molecular diagnostics and disease mechanism

A recurrent EYA1 mutation causing alternative RNA splicing in branchio‐oto‐renal syndrome: Implications for molecular diagnostics and disease mechanism

Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL

Deafness

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