The R245X Mutation of PCDH15 in Ashkenazi Jewish Children Diagnosed with Nonsyndromic Hearing Loss Foreshadows Retinitis Pigmentosa

Brownstein, Zippora; Ben-Yosef, Tamar; Dagan, Orit; Frydman, Moshe; Abeliovich, Dvorah; Sagi, Michal; Abraham, Fabian A.; Taitelbaum-Swead, Riki; Shohat, Mordechai; Hildesheimer, Minka; Friedman, Thomas B.; Avraham, Karen B.

doi:10.1203/01.pdr.0000125258.58267.56

Cited by 30 publications

(19 citation statements)

References 34 publications

(45 reference statements)

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“…Without a careful ophthalmologic evaluation to confirm RP in a young patient, the early onset development of an USH phenotype might be missed and incompletely diagnosed as non-syndromic hearing loss 36. The CDH23 compound heterozygotes from families LMG247 and LMG132, who appeared to have only non-syndromic deafness, were thoroughly evaluated by ophthalmologists at the NIH Clinical Center to confirm the absence of RP.…”

Section: Discussionmentioning

confidence: 99%

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

Schultz

Bhatti

Madeo

et al. 2011

Journal of Medical Genetics

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One DFNB12 allele in trans configuration to an USH1D allele of CDH23 preserves vision and balance in deaf individuals, indicating that the DFNB12 allele is phenotypically dominant to an USH1D allele. This finding has implications for genetic counselling and the development of therapies for retinitis pigmentosa in Usher syndrome. ACCESSION NUMBERS: The cDNA and protein Genbank accession numbers for CDH23 and cadherin 23 used in this paper are AY010111.2 and AAG27034.2, respectively.

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Section: Discussionmentioning

confidence: 99%

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

Schultz

Bhatti

Madeo

et al. 2011

Journal of Medical Genetics

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“…36 The R245X mutation of the gene was detected among a large proportion of cases of USH1 in this population. 37 USH1C, identified mainly among the Acadian population of Louisiana, 38,39 has also been detected in diverse ethnic groups. 40 The genetic cause of USH1 generally leads to a typical USH 1 phenotype.…”

Section: Ush Is Clinically and Genetically Heterogeneousmentioning

confidence: 99%

Genetics and pathological mechanisms of Usher syndrome

2010

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Usher syndrome (USH) comprises a group of autosomal recessively inherited disorders characterized by a dual sensory impairment of the audiovestibular and visual systems. Three major clinical subtypes (USH type I, USH type II and USH type III) are distinguished on the basis of the severity of the hearing loss, the presence or absence of vestibular dysfunction and the age of onset of retinitis pigmentosa (RP). Since the cloning of the first USH gene (MYO7A) in 1995, there have been remarkable advances in elucidating the genetic basis for this disorder, as evidence for 11 distinct loci have been obtained and genes for 9 of them have been identified. The USH genes encode proteins of different classes and families, including motor proteins, scaffold proteins, cell adhesion molecules and transmembrane receptor proteins. Extensive information has emerged from mouse models and molecular studies regarding pathogenesis of this disorder and the wide phenotypic variation in both audiovestibular and/or visual function. A unifying hypothesis is that the USH proteins are integrated into a protein network that regulates hair bundle morphogenesis in the inner ear. This review addresses genetics and pathological mechanisms of USH. Understanding the molecular basis of phenotypic variation and pathogenesis of USH is important toward discovery of new molecular targets for diagnosis, prevention and treatment of this debilitating disorder.

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“…While the auditory deWcit can be successfully treated with cochlear implants (Brownstein et al 2004;Pennings et al 2006), to date there is no eVective treatment for the ophthalmic component of USH1.…”

Section: Introductionmentioning

confidence: 99%

In vitro and ex vivo suppression by aminoglycosides of PCDH15 nonsense mutations underlying type 1 Usher syndrome

et al. 2007

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Type 1 Usher syndrome (USH1) is a recessively inherited condition, characterized by profound prelingual deafness, vestibular areflexia, and prepubertal onset of retinitis pigmentosa (RP). While the auditory component of USH1 can be treated by cochlear implants, to date there is no effective treatment for RP. USH1 can be caused by mutations in each of at least six genes. While truncating mutations of these genes cause USH1, some missense mutations of the same genes cause nonsyndromic deafness. These observations suggest that partial or low level activity of the encoded proteins may be sufficient for normal retinal function, although not for normal hearing. In individuals with USH1 due to nonsense mutations, interventions enabling partial translation of a full-length functional protein may delay the onset and/or progression of RP. One such possible therapeutic approach is suppression of nonsense mutations by small molecules such as aminoglycosides. We decided to test this approach as a potential therapy for RP in USH1 patients due to nonsense mutations. We initially focused on nonsense mutations of the PCDH15 gene, underlying USH1F. Here, we show suppression of several PCDH15 nonsense mutations, both in vitro and ex vivo. Suppression was achieved both by commercial aminoglycosides and by NB30, a new aminoglycoside-derivative developed by us. NB30 has reduced cytotoxicity in comparison to commercial aminoglycosides, and thus may be more efficiently used for therapeutic purposes. The research described here has important implications for the development of targeted interventions that are effective for patients with USH1 caused by various nonsense mutations.

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The R245X Mutation of PCDH15 in Ashkenazi Jewish Children Diagnosed with Nonsyndromic Hearing Loss Foreshadows Retinitis Pigmentosa

Cited by 30 publications

References 34 publications

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

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

Genetics and pathological mechanisms of Usher syndrome

In vitro and ex vivo suppression by aminoglycosides of PCDH15 nonsense mutations underlying type 1 Usher syndrome

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