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Whole-exome analyses of congenital non-syndromic deafness to understand a high-resolution genomic architecture in Indian population

ABSTRACT: Whole-exome analyses of congenital non-syndromic deafness to understand a high-resolution genomic architecture in Indian population

PROVIDER: PRJEB55490 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR10213700.fastq.gz	Fastqsanger.gz
	ERR10213700_1.fastq.gz	Fastqsanger.gz
	ERR10213700_2.fastq.gz	Fastqsanger.gz
	ERR10213701.fastq.gz	Fastqsanger.gz
	ERR10213701_1.fastq.gz	Fastqsanger.gz

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Single cell RNA-seq of cochlear tissues from Tmie+/- and Tmie-/- mice, a model for recessive non-syndromic deafness model 6.

Project description:Deafness is the most common form of sensory impairment in humans and frequently caused by defects in hair cells of the inner ear. Here we demonstrate that in a mouse model for recessive non-syndromic deafness (DFNB6), inactivation of Tmie in hair cells disrupts gene expression in the neurons that innervate them. This includes genes regulating axonal pathfinding and synaptogenesis, two processes that are disrupted in the inner ear of the mutant mice. Similar defects are observed in mouse models for deafness caused by mutations in other genes with primary functions in hair cells. Gene therapy targeting hair cells restores hearing and inner ear circuitry in DFNB6 model mice. We conclude that hair cell function is crucial for the establishment of peripheral auditory circuitry. Treatment modalities for deafness thus need to consider restoration of the function of both hair cells and neurons, even when the primary defect occurs in hair cells.

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A Collaborative Search for New Genes for Non-Syndromic Deafness

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

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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Project description:Mutations in GJB2 (Gap junction protein beta 2) are the most common genetic cause of non-syndromic hereditary deafness in humans, especially the 35delG and 235delC mutations. Owing to the homozygous-lethal of Gjb2 mutation in mice, there are currently no perfect mouse models carrying Gjb2 mutation to mimic human hereditary deafness and unveil the pathogenesis. Here, we first constructed heterozygous mutant mice, Gjb2+/35delG and Gjb2+/235delC, through androgenic haploid embryonic stem cells (AG-haESCs) mediated semi-cloning technology, which showed normal hearing function at P28. Furthermore, a homozygous mutant mouse model, Gjb235delG/35delG, was generated via enhanced tetraploid embryo complementation, which exhibited profound hearing loss like human patients at P14. Mechanism analysis showed that Gjb2 35delG disrupts the formation of intercellular gap junction channel and tunnel of Corti, and hair cell mechanotransduction, rather than the development of hair cells. Collectively, our study provides ideal mouse models for understanding the pathogenic mechanism and opens up a new avenue for investigating the treatment for DFNB1A-related hereditary deafness.

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