Inherited retinal diseases (IRDs), which are among the most common genetic diseases in humans, define a clinically and genetically heterogeneous group of disorders. Over 80 forms of syndromic IRDs have been described. Approximately 200 genes are associated with these syndromes. The majority of syndromic IRDs are recessively inherited and rare. Many, although not all, syndromic IRDs can be classified into one of two major disease groups: inborn errors of metabolism and ciliopathies. Besides the retina, the systems and organs most commonly involved in syndromic IRDs are the central nervous system, ophthalmic extra-retinal tissues, ear, skeleton, kidney and the cardiovascular system. Due to the high degree of phenotypic variability and phenotypic overlap found in syndromic IRDs, correct diagnosis based on phenotypic features alone may be challenging and sometimes misleading. Therefore, genetic testing has become the benchmark for the diagnosis and management of patients with these conditions, as it complements the clinical findings and facilitates an accurate clinical diagnosis and treatment.

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of diseases that cause vision loss due to abnormal development or due to the dysfunction or degeneration of the photoreceptors or the retinal pigment epithelium

Mutations in S-phase Cyclin A Associated Protein in the Endoplasmic Reticulum (SCAPER) cause a recessively-inherited multi-systemic disorder whose main features are retinal degeneration and intellectual disability. SCAPER, originally identified as a cell-cycle regulator, was also suggested to be a ciliary protein. Because Scaper mutant males are sterile, we set up to characterize their phenotype. Testes of Scaper mutant mice are significantly smaller than those of WT mice. Histology revealed no signs of spermatogenesis and seminiferous tubules contained mainly Sertoli cells with a few spermatogonia/spermatogonial stem cells (SSCs). In WT testes, SCAPER is expressed by SSCs and in the various stages of spermatogenesis, as well as in Sertoli cells. In WT spermatozoa SCAPER is not expressed in the flagellum but rather in the head compartment, where it is found both in the nucleus and in the peri-nuclear region. Scaper mutant females present reduced fertility, manifested by a significantly smaller litter size compared to WT females. Mutant ovaries are similar in size, but comprised of significantly less primordial and antral follicles, compared to WT ovaries, while the number of atretic follicles is significantly higher. In WT ovarian follicles SCAPER is expressed in the somatic granulosa cells as well as in the oocyte. In conclusion, our data demonstrate that SCAPER is a crucial component in both male and female reproductive systems. We hypothesize that the reproductive phenotype observed in Scaper mutant mice is rooted in SCAPER’s interaction with Cyclin A/Cdk2, which play an important role, however different, in male and female gonads.

Photoreceptor disc component (PRCD) is a small protein which is exclusively localized to photoreceptor outer segments, and is involved in the formation of photoreceptor outer segment discs. Mutations in PRCD are associated with retinal degeneration in humans, mice, and dogs. The purpose of this work was to identify PRCD-binding proteins in the retina. PRCD protein-protein interactions were identified when implementing the Ras recruitment system (RRS), a cytoplasmic-based yeast two-hybrid system, on a bovine retina cDNA library. An interaction between PRCD and tubby-like protein 1 (TULP1) was identified. Co-immunoprecipitation in transfected mammalian cells confirmed that PRCD interacts with TULP1, as well as with its homolog, TUB. These interactions were mediated by TULP1 and TUB highly conserved C-terminal tubby domain. PRCD localization was altered in the retinas of TULP1- and TUB-deficient mice. These results show that TULP1 and TUB, which are involved in the vesicular trafficking of several photoreceptor proteins from the inner segment to the outer segment, are also required for PRCD exclusive localization to photoreceptor outer segment discs.

Purpose: To identify the genetic basis for retinitis pigmentosa (RP) in a cohort of Jewish patients from Caucasia. Methods: Patients underwent a detailed ophthalmic evaluation, including funduscopic examination, visual field testing, optical coherence tomography (OCT), and electrophysiological tests, electroretinography (ERG) and visual evoked potentials (VEP). Genetic analysis was performed with a combination of whole exome sequencing (WES) and Sanger sequencing. Bioinformatic analysis of the WES results was performed via a customized pipeline. Pathogenicity of the identified intronic variant was evaluated in silico using the web tool Human Splicing Finder, and in vitro, using a minigene-based splicing assay. Linkage disequilibrium (LD) analysis was used to demonstrate a founder effect, and the decay of LD over generations around the mutation in Caucasus Jewish chromosomes was modeled to estimate the age of the most recent common ancestor. Results: In eight patients with RP from six unrelated families, all of Caucasus Jewish ancestry, we identified a novel homozygous intronic variant, located at position -9 of PDE6B intron 15. The c.1921-9C>G variant was predicted to generate a novel acceptor splice site, nine bases upstream of the original splice site of intron 15. In vitro splicing assay demonstrated that this novel acceptor splice site is used instead of the wild-type site, leading to an 8-bp insertion into exon 16, which is predicted to cause a frameshift. The presence of a common ancestral haplotype in mutation-bearing chromosomes was compatible with a founder effect. Conclusions: The PDE6B c.1921-9C>G intronic mutation is a founder mutation that accounts for at least 40% (6/15 families) of autosomal recessive RP among Caucasus Jews. This result is highly important for molecular diagnosis, carrier screening, and genetic counseling in this population.