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.

Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities

“…CLRN1 (Clarin-1) and HARS (histidyl-tRNA synthetase) are the USH3 genes [25, 40–42]. Furthermore, PDZD7 (PDZ domain containing 7) was recently discovered as an USH modifier and digenic USH contributor gene [26], and CEP250 as an atypical USH gene [27]. Among these genes, HARS is debatable as an USH3 gene, because patients carrying mutations in this gene develop episodic psychosis as well as progressive hearing loss and RP [25], which could be clinical symptoms of other rare syndromes.…”

Molecular Genetics of the Usher Syndrome in Lebanon: Identification of 11 Novel Protein Truncating Mutations by Whole Exome Sequencing

“…Mutations in one gene CLRN1 are found causative for USH3 [18]. Digenic inheritance in USH has been reported with mutations in GPR98 and PDZD7 [19] in USH2 patients and with mutations in CDH23 and PCDH15 [ 20 ] or MYO7A and PCDH15 [ 21 ] in USH1 patients. In addition, mutations in MYO7A, USH1C, DFNB31, CIB2, CDH23 and PCDH15 were also reported in non-syndromic deafness without retinal degeneration [22], [23] and mutations in USH2A and CLRN1 have been reported in patients with isolated RP or retinal dystrophies and no deafness [24]–[26].…”

Novel recessive PDZD7 biallelic mutations in two Chinese families with non‐syndromic hearing loss

“…PDZD7 encodes a PDZ domain‐containing scaffold protein; the largest transcript (NM_001195263.1) of PDZD7 encodes 17 exons, and it has been implicated as an ARNSHL‐associated gene (Booth et al, 2015; Le Quesne Stabej et al, 2017; Schneider et al, 2009; Vona et al, 2016) and a modifier and candidate gene for human USH2 (Ebermann et al, 2010). In this study, next generation sequencing (NGS) was used to find the disease‐causing gene of two Chinese families with ARNSHL (Figure 1a and 1b), and we identified two biallelic mutations in the PDZD7 gene.…”

“…Early symptoms of RP include night blindness and loss of peripheral vision. However, to date, only monoallelic mutations in the PDZD7 gene act as a retinal disease modifier of homozygous USH2A mutations and a contributor of digenic inheritance with GPR98 in USH2 patients (Ebermann et al, 2010). The PDZD7 mutation p.Arg56Profs*24 (c.166_167 insC) was suggested to be a retinal phenotype modifier in Usher syndrome in its heterozygous state.…”

“…Variations in many genes can cause either non‐syndromic hearing loss or syndromic hearing loss. PDZD7 encodes a PDZ domain‐containing scaffold protein, that was recently implicated as a modifier and candidate gene in human USH2 (Ebermann et al, 2010), and it is an autosomal recessive genetic hearing loss (ARNSHL)‐associated gene (Booth et al, 2015; Le Quesne Stabej et al, 2017; Schneider et al, 2009; Vona et al, 2016). The PDZD7 gene was first identified as being responsible for ARNSHL in a consanguineous German family in 2009.…”