Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes

Schultz, Julie M.; Bhatti, Rashid; Madeo, Anne C.; Turriff, Amy; Muskett, Julie; Zalewski, Christopher; King, Kelly A.; Ahmed, Zubair M.; Riazuddin, Saima; Ahmad, Nisar; Hussain, Zawar; Qasim, Muhammad; Kahn, Shaheen; Meltzer, Meira; Liu, Xue Z.; Munisamy, Murali; Ghosh, Manju; Rehm, Heidi L.; Tsilou, Ekaterini; Griffith, Andrew J.; Zein, Wadih M.; Brewer, Carmen C.; Riazuddin, Sheikh; Friedman, Thomas B.

doi:10.1136/jmedgenet-2011-100262

Cited by 92 publications

(91 citation statements)

References 52 publications

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“…In contrast, a recent study reported that one hypomorphic CDH23 allele in trans configuration to a null CDH23 allele preserves vision and balance in deaf individuals [28]. Moreover, no allelic variants of CDH23 that cause RP or vestibular dysfunction with normal hearing have been reported [1, 4, 5, 28]. These results indicate that hypomorphic CDH23 alleles are phenotypically dominant to null CDH23 alleles and that hearing is more affected by CDH23 mutations than vision or vestibular function.…”

Section: Discussionmentioning

confidence: 96%

“…Some compound heterozygotes with one functionally null allele and one hypomorphic allele of CDH23 have an Usher phenotype [1]. In contrast, a recent study reported that one hypomorphic CDH23 allele in trans configuration to a null CDH23 allele preserves vision and balance in deaf individuals [28]. Moreover, no allelic variants of CDH23 that cause RP or vestibular dysfunction with normal hearing have been reported [1, 4, 5, 28].…”

Section: Discussionmentioning

confidence: 99%

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Compound Heterozygosity of the Functionally Null Cdh23v-ngt and Hypomorphic Cdh23ahl Alleles Leads to Early-onset Progressive Hearing Loss in Mice

et al. 2013

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The waltzer (v) mouse mutant harbors a mutation in Cadherin 23 (Cdh23) and is a model for Usher syndrome type 1D, which is characterized by congenital deafness, vestibular dysfunction, and prepubertal onset of progressive retinitis pigmentosa. In mice, functionally null Cdh23 mutations affect stereociliary morphogenesis and the polarity of both cochlear and vestibular hair cells. In contrast, the murine Cdh23ahl allele, which harbors a hypomorphic mutation, causes an increase in susceptibility to age-related hearing loss in many inbred strains. We produced congenic mice by crossing mice carrying the v niigata (Cdh23v-ngt) null allele with mice carrying the hypomorphic Cdh23ahl allele on the C57BL/6J background, and we then analyzed the animals’ balance and hearing phenotypes. Although the Cdh23v-ngt/ahl compound heterozygous mice exhibited normal vestibular function, their hearing ability was abnormal: the mice exhibited higher thresholds of auditory brainstem response (ABR) and rapid age-dependent elevation of ABR thresholds compared with Cdh23ahl/ahl homozygous mice. We found that the stereocilia developed normally but were progressively disrupted in Cdh23v-ngt/ahl mice. In hair cells, CDH23 localizes to the tip links of stereocilia, which are thought to gate the mechanoelectrical transduction channels in hair cells. We hypothesize that the reduction of Cdh23 gene dosage in Cdh23v-ngt/ahl mice leads to the degeneration of stereocilia, which consequently reduces tip link tension. These findings indicate that CDH23 plays an important role in the maintenance of tip links during the aging process.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Compound Heterozygosity of the Functionally Null Cdh23v-ngt and Hypomorphic Cdh23ahl Alleles Leads to Early-onset Progressive Hearing Loss in Mice

et al. 2013

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“…CDH23, contributing to Leber optic atrophy and the three close diseases, is underlying the genetic overlap of 171 disease pairs; COL7A1, contributing to ARMD1 and the three close diseases, is underlying the genetic overlap of 1085 disease pairs. Mutations within both genes are shown in the literature (Schultz et al, 2011;Dighiero et al, 2004) to potentially cause vision loss. In contrast, the 32 genes underlying the genetic overlap of cataract, RP, and CBD include genes that are more specific to the three diseases, therefore contributing more significantly to their genetic overlap.…”

Section: Genetic Overlaps Among Diseases 119mentioning

confidence: 99%

Finding Genetic Overlaps Among Diseases Based on Ranked Gene Lists

Chen

Zhou²,

Sun³

2015

Journal of Computational Biology

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To understand disease relationships in terms of their genetic mechanisms, it is important to study the common genetic basis among different diseases. Although discoveries on pleiotropic genes related to multiple diseases abound, methods flexibly applicable to various types of datasets generated from different studies or experiments are needed to gain big pictures on the genetic relationships among a large number of diseases. We develop a set of genetic similarity measures to gauge the genetic overlap between diseases, as well as several estimators of the number of overlapping disease genes between diseases. These methods are based on ranked gene lists so that they could be flexibly applied to different types of data. We first investigate the performance of the genetic similarity measure for evaluating the similarity between human diseases in simulation studies. Then we apply the method to diseases in the OMIM database. We show that our proposed genetic measure achieves superior performance in explaining phenotype similarities between diseases compared to simpler methods. Furthermore, we identified common genes underlying the genetic overlap between disease pairs. With an example of five vision-related diseases, we demonstrate how our methods can provide insights into the relationships among diseases based on their shared genetic mechanisms.

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“…Mutations in their corresponding genes are associated with Usher syndrome type I and nonsyndromic hearing loss (Bolz et al, 2001;Ahmed et al, 2003Ahmed et al, , 2006Schultz et al, 2011). Several interactions between these and other Usher proteins have been described (Reiners et al, 2006;Zallocchi et al, 2010Zallocchi et al, , 2012aCaberlotto et al, 2011).…”

Section: Clarin-1 Interaction With the Mechanotransduction Machinerymentioning

confidence: 99%

Clarin-1 acts as a modulator of mechanotransduction activity and presynaptic ribbon assembly

Ogun¹,

Zallocchi²

2014

J Gen Physiol

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Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes

Cited by 92 publications

References 52 publications

Compound Heterozygosity of the Functionally Null <i>Cdh23<sup>v-ngt</sup></i> and Hypomorphic <i>Cdh23<sup>ahl</sup></i> Alleles Leads to Early-onset Progressive Hearing Loss in Mice

Compound Heterozygosity of the Functionally Null <i>Cdh23<sup>v-ngt</sup></i> and Hypomorphic <i>Cdh23<sup>ahl</sup></i> Alleles Leads to Early-onset Progressive Hearing Loss in Mice

Finding Genetic Overlaps Among Diseases Based on Ranked Gene Lists

Clarin-1 acts as a modulator of mechanotransduction activity and presynaptic ribbon assembly

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