Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%

Roux, Anne Françoise; Faugère, Valérie; Guedard, S. Le; Pallares-Ruiz, Nathalie; Vielle, Anne; Chambert, Sylvie; Marlin, Sandrine; Hamel, Christian; Gilbert, Brigitte; Malcolm, Sue; Claustres, Mireille

doi:10.1136/jmg.2006.041954

Cited by 99 publications

(95 citation statements)

References 23 publications

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“…11 Sequence variants affecting the function of the PCDH15 gene, located at chromosome 10q21-22, are identified in 11-19% of the USH1 patients. [12][13][14] Function-affecting variants in PCDH15 may not only lead to USH1, but also to autosomal recessive nonsyndromic profound hearing impairment (DFNB23). 12 Most patients with USH2, including patients from Denmark, have function-affecting variants in USH2A, [15][16][17][18][19] which is located on chromosome 1.…”

Section: Introductionmentioning

confidence: 99%

Partial USH2A deletions contribute to Usher syndrome in Denmark

et al. 2015

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Usher syndrome is an autosomal recessive disorder characterized by congenital hearing impairment, progressive visual loss owing to retinitis pigmentosa and in some cases vestibular dysfunction. Usher syndrome is divided into three subtypes, USH1, USH2 and USH3. Twelve loci and eleven genes have so far been identified. Duplications and deletions in PCDH15 and USH2A that lead to USH1 and USH2, respectively, have previously been identified in patients from United Kingdom, Spain and Italy. In this study, we investigate the proportion of exon deletions and duplications in PCDH15 and USH2A in 20 USH1 and 30 USH2 patients from Denmark using multiplex ligation-dependent probe amplification (MLPA). Two heterozygous deletions were identified in USH2A, but no deletions or duplications were identified in PCDH15. Next-generation mate-pair sequencing was used to identify the exact breakpoints of the two deletions identified in USH2A. Our results suggest that USH2 is caused by USH2A exon deletions in a small fraction of the patients, whereas deletions or duplications in PCDH15 might be rare in Danish Usher patients.

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Section: Introductionmentioning

confidence: 99%

Partial USH2A deletions contribute to Usher syndrome in Denmark

et al. 2015

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“…Mutations that lead to predicted CDH23 null alleles cause USH1D (Fig. 2D) (1)(2)(3)(4)(5)(7)(8)(9)(10)(11)(12), which is modeled by mutations in waltzer mice (Fig. 2D) (27,33,34).…”

Section: Resultsmentioning

confidence: 99%

“…The cadherin 23 gene (CDH23) provides a striking example. Predicted CDH23 null mutations lead to deaf-blindness (USH1D), whereas missense mutations cause nonsyndromic deafness (DFNB12) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). A polymorphism in Cdh23 is linked to age-related hearing loss (14).…”

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A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells

Schwander

Xiong

Tokita

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Deafness is the most common form of sensory impairment in humans and is frequently caused by single gene mutations. Interestingly, different mutations in a gene can cause syndromic and nonsyndromic forms of deafness, as well as progressive and age-related hearing loss. We provide here an explanation for the phenotypic variability associated with mutations in the cadherin 23 gene (CDH23). CDH23 null alleles cause deaf-blindness (Usher syndrome type 1D; USH1D), whereas missense mutations cause nonsyndromic deafness (DFNB12). In a forward genetic screen, we have identified salsa mice, which suffer from hearing loss due to a Cdh23 missense mutation modeling DFNB12. In contrast to waltzer mice, which carry a CDH23 null allele mimicking USH1D, hair cell development is unaffected in salsa mice. Instead, tip links, which are thought to gate mechanotransduction channels in hair cells, are progressively lost. Our findings suggest that DFNB12 belongs to a new class of disorder that is caused by defects in tip links. We propose that mutations in other genes that cause USH1 and nonsyndromic deafness may also have distinct effects on hair cell development and function.cadherin 23 ͉ Cdh23 ͉ Usher syndrome ͉ progressive hearing loss

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“…The single condition touchdown amplification/ sequencing strategy is now widely used in our laboratory, eg, for the comprehensive genotyping of eight genes in the Usher syndrome, for which up to 250 amplicons are analyzed. 28,29 The new fluorescent, rapid, and reliable method that we report here for the determination of alleles and haplotypes at locus IVS8-(TG)mTn will also facilitate the genotyping of the sequences that modulate the splicing efficiency of exon 9 in the mRNA and/or are major determinants of the penetrance of the T5 allele in CBAVD. The importance of IVS8-(TG)mT5 determination is supported by an international collaborative study providing evidence that the odds of pathogenicity are 28 and 34 times greater for (TG)12T5 and (TG)13T5, respectively, than for (TG)11T5.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive and Rapid Genotyping of Mutations and Haplotypes in Congenital Bilateral Absence of the Vas Deferens and Other Cystic Fibrosis Transmembrane Conductance Regulator-Related Disorders

Bareil

Guittard

Altiéri

et al. 2007

The Journal of Molecular Diagnostics

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Available commercial kits only screen for the most common cystic fibrosis transmembrane conductance regulator (CFTR) mutations causing classic cystic fibrosis and for the Tn variant in IVS8. However, full scanning of CFTR is needed for the diagnosis of patients with cystic fibrosis or CFTR-related disorders (including congenital bilateral absence of the vas deferens) bearing rare mutations. Standard strategies for detecting point mutations rely on extensive scanning of the gene by denaturing gradient gel electrophoresis or denaturing high performance liquid chromatography, which are time-consuming. Moreover, the haplotyping of IVS8-(TG)m and Tn tracts is still challenging despite several recent improvements. We have optimized both the detection of mutations and the haplotyping of IVS8 polyvariants in developing two methods: i) a rapid and robust direct sequence analysis of all exons/flanking introns of the CFTR gene based on single condition touchdown amplification/sequencing in 96-well plates, and ii) a fluorescent assay that allows haplotyping of IVS8-(TG)mTn even without family linkage study. Combined with search for rare large rearrangements, this strategy detected 87.9% of CFTR defects in congenital bilateral absence of the vas deferens patients, a proportion considerably higher than those usually reported. These highly efficient tests, scanning each sample in a few days, greatly improve the genotyping of patients with CFTR-related symptoms and may be particularly important in emergency situations such as fetus with hyperechogenic bowel suggestive of cystic fibrosis. (J Mol Diagn 2007, 9:582-588;

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Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%

Abstract: Diagnostic testing for USH1 is feasible with a high rate of detection and can be made more efficient by selecting a candidate gene by preliminary linkage and haplotype analysis.

Cited by 99 publications

References 23 publications

Partial USH2A deletions contribute to Usher syndrome in Denmark

Partial USH2A deletions contribute to Usher syndrome in Denmark

A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells

Comprehensive and Rapid Genotyping of Mutations and Haplotypes in Congenital Bilateral Absence of the Vas Deferens and Other Cystic Fibrosis Transmembrane Conductance Regulator-Related Disorders

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