PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome
Inga Ebermann, Jennifer B. Phillips, Max C. Liebau, Robert K. Koenekoop, Bernhard Schermer, Irma Lopez, Ellen Schäfer, Anne-Francoise Roux, Claudia Dafinger, Antje Bernd, Eberhart Zrenner, Mireille Claustres, Bernardo Blanco, Gudrun Nürnberg, Peter Nürnberg, Rebecca Ruland, Monte Westerfield, Thomas Benzing, Hanno J. Bolz
Inga Ebermann, Jennifer B. Phillips, Max C. Liebau, Robert K. Koenekoop, Bernhard Schermer, Irma Lopez, Ellen Schäfer, Anne-Francoise Roux, Claudia Dafinger, Antje Bernd, Eberhart Zrenner, Mireille Claustres, Bernardo Blanco, Gudrun Nürnberg, Peter Nürnberg, Rebecca Ruland, Monte Westerfield, Thomas Benzing, Hanno J. Bolz
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Research Article Ophthalmology

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

Abstract

Usher syndrome is a genetically heterogeneous recessive disease characterized by hearing loss and retinitis pigmentosa (RP). It frequently presents with unexplained, often intrafamilial, variability of the visual phenotype. Although 9 genes have been linked with Usher syndrome, many patients do not have mutations in any of these genes, suggesting that there are still unidentified genes involved in the syndrome. Here, we have determined that mutations in PDZ domain–containing 7 (PDZD7), which encodes a homolog of proteins mutated in Usher syndrome subtype 1C (USH1C) and USH2D, contribute to Usher syndrome. Mutations in PDZD7 were identified only in patients with mutations in other known Usher genes. In a set of sisters, each with a homozygous mutation in USH2A, a frame-shift mutation in PDZD7 was present in the sister with more severe RP and earlier disease onset. Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein–coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus. We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Our data challenge the view of Usher syndrome as a traditional Mendelian disorder and support the reclassification of Usher syndrome as an oligogenic disease.

Authors

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

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Figure 2

PDZD7 mutations in Usher syndrome type 2 families.

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PDZD7 mutations in Usher syndrome type 2 families. (A) Homozygosity...
(A) Homozygosity for p.C1447QfsX29USH2A in FCa and FCb. The retinal phenotype is more severe in FCa, who carries a de novo PDZD7 mutation, p.R56PfsX24. (B) GER1 is double heterozygous for p.R1505SfsX7USH2A and a PDZD7 splice site alteration (causing in-frame inclusion of either 16 or 68 unrelated amino acids). The latter may represent a benign variant that does not contribute to the phenotype. (C) Evidence for digenic inheritance due to double heterozygosity for truncating mutations in GPR98 (USH2C), p.A5713LfsX3, and PDZD7, p.C732LfsX18, in GER2. The healthy sister carries the PDZD7 deletion but not the GPR98 mutation. (D) In family U329, 4 siblings carry the PDZD7 mutation p.R56PfsX24 in heterozygous state. Microsatellite marker and sequence analyses largely excluded a second mutation in PDZD7. The index patient, U329-1, carries a heterozygous missense change, p.L3160F, in MYO15A (not shown). Different PDZD7 alleles are indicated by colors. Samples from the parents (first generation cousins) were not available. U329-2 has high frequency hearing loss and a history of long-term working in a noisy environment. U329-4 has asymmetric hearing loss (mild/severe) that is probably unrelated to the hearing impairment in U329-1. IVS1 and IVS10 denote polymorphic CA-repeats (not annotated).