PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Ebermann, Inga; Phillips, Jennifer B.; Liebau, Max C.; Koenekoop, Robert K.; Schermer, Bernhard; López, Irma; Schafer, Ellen J.; Roux, Anne‐Françoise; Dafinger, Claudia; Bernd, Antje; Zrenner, Eberhart; Claustres, Mireille; Blanco, Bernardo; Nürnberg, Gudrun; Nürnberg, Peter; Ruland, Rebecca; Westerfield, Monte; Benzing, Thomas; Bolz, Hanno J.

doi:10.1172/jci46312

Cited by 49 publications

(80 citation statements)

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“…Specifically, a heterozygous mutant allele of PDZD7 exacerbates the course of retinitis pigmentosa in subjects carrying a heterozygous truncation mutation of USH2A or GPR98 in trans with the heterozygous mutant allele of PDZD7. 25 Therefore, it was proposed that a subset of Usher syndrome may not be a Mendelian but a digenic or oligogenic disease. 25 This suggestion is compatible with later observations that PDZD7 colocalized with usherin, whirlin, and GPR98 to the ankle-link region, 25 as well as with observations that cytosolic domains of usherin and GPR98 can bind to PDZD7.…”

Section: Genetics In Medicine | Volume 17 | Number 11 | November 2015mentioning

confidence: 99%

“…25 Therefore, it was proposed that a subset of Usher syndrome may not be a Mendelian but a digenic or oligogenic disease. 25 This suggestion is compatible with later observations that PDZD7 colocalized with usherin, whirlin, and GPR98 to the ankle-link region, 25 as well as with observations that cytosolic domains of usherin and GPR98 can bind to PDZD7. 26 Based on these observations, the role of PDZD7 was predicted to be involved in ankle-link complex scaffolding components.…”

Section: Genetics In Medicine | Volume 17 | Number 11 | November 2015mentioning

confidence: 99%

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Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population

Kim

Park

et al. 2015

Genetics in Medicine

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Purpose: This study was designed to delineate genetic contributions, if any, to sporadic forms of mild to moderate sensorineural hearing loss (SNHL) not related to GJB2 mutations (DFNB1) in a pediatric population. Methods:We recruited 11 non-DFNB1 simplex cases of mild to moderate SNHL in children. We applied whole-exome sequencing to all 11 probands. We used a filtering strategy assuming that de novo variants of known autosomal dominant (AD) deafness genes, biallelic mutations in autosomal recessive (AR) genes, monoallelic mutations in X chromosome genes for males, and digenic inheritance could be associated. Candidate variants first were prioritized with allele frequency in public databases and confirmed by a phase or a segregation test in each family. Additional information from the literature or public databases was used to identify strong candidate variants.Results: Strong candidate variants were detected in 5 of 11 probands (45.4%). A diverse mode of inheritance implicated the sporadic occurrence of the phenotype. AR mutations in OTOGL and SERPINB6 and digenic inheritance involving two deafness genes, GPR98 and PDZ7, were detected. A de novo AD mutation also was detected in TECTA and MYH14. No syndromic feature was detected in individuals with GPR98/PDZ7 or MYH14 variants in our cohort at this moment. Conclusion:Mild to moderate pediatric SNHL, even if sporadic, features a strong genetic etiology and can manifest via diverse modes of inheritance. In addition, a multidisciplinary approach should be used for a correct diagnosis. Genet Med advance online publication 26 February 2015

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Section: Genetics In Medicine | Volume 17 | Number 11 | November 2015mentioning

confidence: 99%

Section: Genetics In Medicine | Volume 17 | Number 11 | November 2015mentioning

confidence: 99%

Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population

Kim

Park

et al. 2015

Genetics in Medicine

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“…Although morpholino-induced knockdown of ush2a or pdzd7a alone resulted in moderate levels of photoreceptor cell death in the retina, combined morpholino-induced partial ush2a; pdzd7a, or pdzd7a;gpr98 knockdown exacerbated photoreceptor death, consistent with the possibility of human digenic inheritance of USH-associated mutations and retinal disease modifiers in patients with USH2A. 85 Point mutations and large deletions in PCDH15 are the cause of human USH1. 86,87 Reduction in the zebrafish orthologue pcdh15b resulted in short and disorganised outer segments that lack interdigitation with the RPE.…”

Section: Retinitis Pigmentosamentioning

confidence: 75%

The zebrafish eye—a paradigm for investigating human ocular genetics

Richardson¹,

Tracey‐White²,

Webster

et al. 2016

Eye

153

162

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Although human epidemiological and genetic studies are essential to elucidate the aetiology of normal and aberrant ocular development, animal models have provided us with an understanding of the pathogenesis of multiple developmental ocular malformations. Zebrafish eye development displays in depth molecular complexity and stringent spatiotemporal regulation that incorporates developmental contributions of the surface ectoderm, neuroectoderm and head mesenchyme, similar to that seen in humans. For this reason, and due to its genetic tractability, external fertilisation, and early optical clarity, the zebrafish has become an invaluable vertebrate system to investigate human ocular development and disease. Recently, zebrafish have been at the leading edge of preclinical therapy development, with their amenability to genetic manipulation facilitating the generation of robust ocular disease models required for large-scale genetic and drug screening programmes. This review presents an overview of human and zebrafish ocular development, genetic methodologies employed for zebrafish mutagenesis, relevant models of ocular disease, and finally therapeutic approaches, which may have translational leads in the future.

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“…10 Furthermore, the USH2 modifier gene, PDZD7, has been recognized. 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).…”

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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PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Abstract: Tim-3 expression on PD-1 + HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocytedirected in vitro cytotoxicity

Cited by 49 publications

References 0 publications

Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population

Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population

The zebrafish eye—a paradigm for investigating human ocular genetics

Partial USH2A deletions contribute to Usher syndrome in Denmark

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