Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies

Abstract

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 spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.

A comprehensive portrait of cilia and ciliopathies from a CRISPR-based screen for Hedgehog signaling

“…ciliopathies. Consistent with this possibility, the peptidyl-prolyl isomerase Cwc27 was a hit in our 10 screen and was recently identified as a retinitis pigmentosa (RP) gene 47 . Although this syndrome 11…”

Human organotypic retinal flat‐mount culture (HORFC) as a model for retinitis pigmentosa11

“…Also, some non-snRNP splicing factors such as DHX38 and CWC27 have been reported associated with arRP. 14,15 The reason as to why mutation in these general splicing factors causes retinal restricted disease is unknown. One explanation might be that the retina has an extensive protein turnover (10% of photoreceptor outer segments renew daily) and a high alternative splicing rate, and are more sensitive than other tissues to disturbance in splicesome assembly.…”

Light at Night Exposure Effects on Differentiation and Cell Cycle in the Rat Liver With Autonomic Nervous System Denervation

“…21 The other element of this complex is CWC27 and retinal degeneration is attributed to the dysregulation of CWC27. 22 Gene ontology revealed that the negative regulation of non-motile cilium assembly, the negative regulation of transforming growth factor beta activation, alphatubulin acetylation, and histamine-induced gastric acid secretion are the 4 major terms which are related to the 13 critical DEGs. It is reported that exposure to LAN mostly affects the body's metabolism.…”