Deep intronic homozygous variation in PSMC3 causes a syndromic neurosensory disorder combining deafness and cataract
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ABSTRACT:
PROVIDER: EGAS00001003942 | EGA |
REPOSITORIES: EGA
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Project description:The association of congenital deafness and early-onset cataracts inherited as a recessive trait is a rare combination described in only a few syndromes with very few genes identified to date. Whole-genome sequencing was performed on 3 patients from independent sibships from a large consanguineous family presenting with severe deafness and early-onset cataracts as part of a variable neurological, sensorial and cutaneous syndrome. Medical assessments and imaging were used to define the phenotype. Genome sequencing was performed to unravel the altered genotype by subsequent bioinformatics analysis based on a specific physiopathological filtering approach. We identified a unique homozygous variant in intron 10 of the PSMC3 gene, encoding the 26S proteasome ATPase ring subunit 5 (Rpt5), with a predicted local splice effect as a new donor site (c.1127+337A>G, p.Ser376Argfs15*) confirmed by RT-PCR. Strikingly, fibroblasts derived from patients carrying the deep intronic homozygous PSMC3 pathogenic variant exhibited strong signs of perturbed protein homeostasis, as evidenced by increased accumulation of intracellular ubiquitin-modified proteins. Most interestingly and in contrast to control cells, patient fibroblasts failed to increase their amount of proteasomes following proteasome inhibition using the TCF11/Nrf1 pathway, indicating that these cells were unable to adapt to proteotoxic stress. By way of 2 different zebrafish assays we further show that loss of function of PSMC3 leads to inner ear development anomalies as well as cataracts alike the patient phenotype. We propose that the PSMC3 proteasome subunit dysfunction leads to a novel human syndrome that includes early onset cataracts and deafness and suggest that Rpt5 plays a major role in inner ear and lens development.
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