Retinitis pigmentosa (RP), the most common form of inherited retinal degeneration, is associated with different groups of genes, including those encoding proteins involved in centriole and cilium biogenesis. Exome sequencing revealed a homozygous nonsense mutation [c.304_305delGA (p. D102*)] in POC5, encoding the Proteome Of Centriole 5 protein, in a patient with RP, short stature, microcephaly and recurrent glomerulonephritis. The POC5 gene is ubiquitously expressed, and immunohistochemistry revealed a distinct POC5 localization at the photoreceptor connecting cilium. Morpholino-oligonucleotide-induced knockdown of poc5 translation in zebrafish resulted in decreased length of photoreceptor outer segments and a decreased visual motor response, a measurement of retinal function. These phenotypes could be rescued by wild-type human POC5 mRNA. These findings demonstrate that Poc5 is important for normal retinal development and function. Altogether, this study presents POC5 as a novel gene involved autosomal recessively inherited RP, and strengthens the hypothesis that mutations in centriolar proteins are important cause of retinal dystrophies.

We performed here a comprehensive analysis of WES data as a tool for identifying large genomic deletions in patients with IRDs. Our analysis indicates that large deletions are relatively frequent (about 10% of our WES cohort) and should be screened when analysing WES data.

We report here novel homozygous mutations in various genes causing USH, extending the spectrum of causative mutations. We also prove combined sequencing techniques as useful tools to identify novel disease-causing mutations. To the best of our knowledge, this is the largest report of a genetic analysis of Israeli and Palestinian families (n = 74) with different USH subtypes.

Purpose Usher syndrome (USH) is the most common syndromic inherited retinal disease, causing retinitis pigmentosa and sensorineural hearing loss. We reported previously that a nonsense mutation in the centrosome-associated protein CEP250 gene (encoding C-Nap1) causes atypical USH in patients of Iranian Jewish origin. To better characterize CEP250 , we aimed to generate and study a knockout (KO) mouse model for Cep250 . Methods Mice heterozygous for a “knockout-first” Cep250 construct were generated and bred with Cre recombinase mice to generate the null allele and produce homozygous Cep250 KO mice. Retinal function was evaluated by full-field electroretinography (ffERG) at variable ages, and retinal structure changes were examined using histological analysis. Hearing thresholds were detected using auditory brainstem response (ABR) at the age of 20 months. Results The Cep250 KO mouse model was generated by activating a construct harboring a deletion of exons 6 and 7. At 6 months, the ffERG was normal, but it decreased gradually with age. For both photopic and scotopic ffERG responses, very low amplitudes were evident at 20 months. Histological analysis confirmed late-onset retinal degeneration. ABR tests illustrated that hearing threshold significantly increased at the age of 20 months. Conclusions Although most USH animal models have normal retinal function and structure, the Cep250 KO mouse model shows both retinal degeneration and hearing loss with a relatively late age of onset. This model may shed more light on CEP250 -associated retinal and hearing deficits and represents an efficient platform for the development of treatment modalities for USH. Translational Relevance Our study demonstrates better understanding of Cep250 -associated retinal and hearing disease in a mouse model and may help in developing more efficient gene therapy modalities.