Ontology highlight
ABSTRACT:
PROVIDER: PRJNA780814 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16955638_1.fastq.gz | Fastqsanger.gz | |||
| SRR16955638_2.fastq.gz | Fastqsanger.gz |
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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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Project description:Disease: Severe congenital deafness, early onset cataracts and various neurological features
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Project description:Background & Aims: Most inflammatory bowel diseases (IBDs) are classic polygenic disorders represented by common alleles. However, multiple determinants of very early-onset IBD characterized by a more extensive disease course remain largely unknown. The present study aimed to define the genetic architecture of pediatric and adult-onset IBDs in the Polish population. Results: Of 82 SNPs validated/replicated for association with IBD, a novel BRD2 (rs1049526) association was found in both pediatric (OR= 2.35) and adult (OR= 2.66) patients. Thirty SNPs were shared between pediatric and adult patients; 22 and 30 were unique to adult-onset and pediatric-onset IBD, respectively. WES identified numerous rare/infrequent, potentially deleterious variants in IBD-associated or innate immunity-associated genes. Both groups of variants were over-represented in affected children. Two highly deleterious homozygous variants, HLA-DRB1 c.565_566insC and NCF4 p.Arg8Trp, were found in two affected children, and WAS p.Glu131Lys was found in one child and one adult patient. Conclusions: Our GWAS revealed differences in the polygenic architecture of pediatric- and adult-onset IBD. A significant accumulation of rare/low frequency deleterious variants in affected children suggests a contribution by yet unexplained genetic components.
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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.
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Project description:To investigate the participation of deafness genes in the genetic program of the superior olivary complex (SOC), a prominent auditory brainstem center, we performed a comparative genome-wide microarray based gene expression analysis of the rat SOC and the rat brain at postnatal days (P) P4 and P25. Data were validated by qRT-PCR. Statistical analyses revealed 912 oligos up-regulated in the SOC at P4 and 1609 at P25. A total of 453 oligos were up-regulated in the SOC at both developmental stages. Subsequently, a list of 138 transcripts associated with hearing-impairment was extracted from publically available databases and literature. 26 of these transcripts were present in SOC-related gene signature lists, whereas only 11 were present in brain-related gene signature lists. Furthermore, in all 3 SOC-related gene signature lists, transcripts associated with hearing impairment were significantly enriched. Finally, there was a tendency of the SOC-related genes to map to human deafness loci with unknown etiology. Altogether, our study identified a tight genetic link between the SOC-related genetic program and deafness genes. The genome wide expression during the postnatal development of the SOC and the brain was investigated at two different time points: at postnatal (P) day 4 (before hearing onset) and at P25 (after hearing onset). Samples were hybridized onto two color platforms. At least 6 up to nine biological replicates per sample were performed.
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