title: 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.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Ebermann
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Phillips
authors.forename: Max C
authors.initials: MC
authors.lastname: Liebau
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schermer
authors.forename: Irma
authors.initials: I
authors.lastname: Lopez
authors.forename: Ellen
authors.initials: E
authors.lastname: Schäfer
authors.forename: Anne-Francoise
authors.initials: AF
authors.lastname: Roux
authors.forename: Claudia
authors.initials: C
authors.lastname: Dafinger
authors.forename: Antje
authors.initials: A
authors.lastname: Bernd
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.forename: Bernardo
authors.initials: B
authors.lastname: Blanco
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ruland
authors.forename: Monte
authors.initials: M
authors.lastname: Westerfield
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.forename: Hanno J
authors.initials: HJ
authors.lastname: Bolz
mesh_terms: D016368:Frameshift Mutation; D005838:Genotype; D034381:Hearing Loss / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics*; D035781:Siblings; D013577:Syndrome; D052245:Usher Syndromes / Q000235:genetics* / Q000378:metabolism
chemical_list: C417525:ADGRV1 protein, human; D043562:Receptors, G-Protein-Coupled