Dataset Information

Deep intronic homozygous variation in PSMC3, a subunit of the 19S proteasome regulatory complex, causes a syndromic neurosensory disorder combining deafness and cataract

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast, Skin Fibroblast

DISEASE(S): Ciliopathy

SUBMITTER: Lauriane Kuhn

LAB HEAD: Jean Muller

PROVIDER: PXD015836 | Pride | 2020-04-28

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	2019_S17_Cstoetzel_PSMC3_CTRL1.mgf	Mgf
	2019_S17_Cstoetzel_PSMC3_CTRL1.pride.mgf.gz	Mgf
	2019_S17_Cstoetzel_PSMC3_CTRL1.raw	Raw
	2019_S17_Cstoetzel_PSMC3_CTRL2.mgf	Mgf
	2019_S17_Cstoetzel_PSMC3_CTRL2.pride.mgf.gz	Mgf

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Publications

Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress.

Kröll-Hermi Ariane A Ebstein Frédéric F Stoetzel Corinne C Geoffroy Véronique V Schaefer Elise E Scheidecker Sophie S Bär Séverine S Takamiya Masanari M Kawakami Koichi K Zieba Barbara A BA Studer Fouzia F Pelletier Valerie V Eyermann Carine C Speeg-Schatz Claude C Laugel Vincent V Lipsker Dan D Sandron Florian F McGinn Steven S Boland Anne A Deleuze Jean-François JF Kuhn Lauriane L Chicher Johana J Hammann Philippe P Friant Sylvie S Etard Christelle C Krüger Elke E Muller Jean J Strähle Uwe U Dollfus Hélène H

EMBO molecular medicine 20200605 7

The ubiquitin-proteasome system degrades ubiquitin-modified proteins to maintain protein homeostasis and to control signalling. Whole-genome sequencing of patients with severe deafness and early-onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome identified a unique deep intronic homozygous variant in the PSMC3 gene, encoding the proteasome ATPase subunit Rpt5, which lead to the transcription of a cryptic exon. The proteasome content and activity in patient's fibrob ...[more]

PMID: 32500975

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Project description:The inner ear in mammals is derived from a simple ectodermal thickening called the otic placode. Through a series of complex morphological changes, the placode forms the mature inner ear comprising of the auditory organ (cochlea) and the vestibular/balance organs (utricle, saccule, and three semi-circular canals). The vast majority of genes known to be involved during inner ear development have been found through mutational screens or by chance. To identify genes that can serve as novel candidates required for inner ear development, and also candidate genes for uncloned human deafnesses, inner ear tissues from mouse embryos from E9 to E15 were microdissected and expression-profiled at half-day intervals. Also profiled was the non-inner ear mesenchymal tissue surrounding the inner ear tissue. Various patterns of gene expression were identified, and significant biological pathways that these genes represented were identified. Also identified were mouse genes whose human orthologs are located within uncloned non-syndromic deafness intervals, thus serving as candidates for sequence analysis. Experiment Overall Design: Inner ear tissues from E9 to E15 were microdissected at half-day intervals. E9 is the earliest stage when the otic placode is clearly visible and able to be microdissected cleanly. E15 is the stage when all the organs of the inner ear have become established, as have the sensory hair and non-sensory support cells within those organs. For each of the stages from E9 to E10, whole inner ears were profiled. For each of the stages from E10.5 to E12, the primordial cochlear and vestibular organs were profiled separately. For each of the stages from E12.5 to E15, the cochlea and the saccule were profiled separately, whereas the utricle and the three ampullae were combined and profiled together. Any given tissue from any given stage was a collection of anywhere between 4 to 17 identical tissues, and was obtained in duplicate (i.e. from different litters). Hence, a total of 58 inner ear samples were obtained. Moreover, non-inner ear tissue found in the immediate vicinity of inner ear tissue was also obtained and profiled. Specifically, all non-inner ear tissue from E9 was profiled in duplicate. Non-inner ear tissue from E9.5 to E10.5 was pooled and profiled together (in duplicate), whereas that from E11 to E15 was pooled and profiled together (also in duplicate). Therefore, a total of 6 non-inner samples were obtained.