Mutations in spliceosome-associated protein homolog CWC27 lead to a spectrum of syndromic and nonsydromic retinal degeneration disease

Abstract

Purpose : Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping phenotypes in humans: skeletal and craniofacial developmental defects or non-syndromic retinitis pigmentosa (RP). We aim at identify additional spliceosome components whose mutation leads to RP.

Methods : Whole exome and whole genome sequencing were performed to identify mutations in a large cohort of patients with inherited retinal diseases. Knock out and knock in mice that carry the same mutation as identified in patients were generated for phenotyping validation and subsequent functional studies.

Results : We have identified CWC27 as the first spliceosome-associated protein that is linked to a spectrum of disease phenotypes when mutated. Mutations in CWC27 have been found in seven unrelated families that show a range of clinical phenotypes, ranging from retinal degeneration coupled with abnormal skeleton, craniofacial, and neurodevelopment defects to nonsyndromic Leber congenital Amaurosis (LCA) and RP. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models. Cwc27 complete knockout mice show significant pre-weaning lethality, and the viable mice present growth retardation and retinal abnormalities. CRISPR-Cas system generated another Cwc27 mutant knock in mouse line with a frameshift mutation near the C-terminal. These mice show no lethality with only retinal degeneration, mimicking the nonsyndromic LCA/RP phenotype.

Conclusions : Our finding established a novel disease-causing gene CWC27 for an LCA/RP-related Mendelian phenotype spectrum. Furthermore, the Cwc27 knock out and knock in mice will serve as unique animal models to reveal the role of spliceosome factors in retinal function maintenance and global development process.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.