New age-related hearing loss candidate genes in humans: an ongoing challenge
| Autor: | Valerio Marino, S. Bassani, Giorgia Girotto, Daniele Dell'Orco, Paolo Gasparini, Anna Morgan, M. Di Stazio, Marco Brumat, P. Garagnani, C. Giuliani |
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| Přispěvatelé: | Di Stazio M., Morgan A., Brumat M., Bassani S., Dell'Orco D., Marino V., Garagnani P., Giuliani C., Gasparini P., Girotto G., Di Stazio, M., Morgan, A., Brumat, M., Bassani, S., Dell'Orco, D., Marino, V., Garagnani, P., Giuliani, C., Gasparini, P., Girotto, G. |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Candidate gene Membrane Transport Protein Cell Cycle Proteins Age-related hearing loss gene discovery Genome-wide association study Protein-Serine-Threonine Kinase Severity of Illness Index Cohort Studies Mice Doublecortin-Like Kinases 0302 clinical medicine HEK293 Cell Cell Cycle Protein Zebrafish Aged 80 and over in vitro studies biology Intracellular Signaling Peptides and Proteins Protein modelling General Medicine Presbycusis Middle Aged Cadherins Italy 030220 oncology & carcinogenesis Models Animal Cohort Female medicine.symptom Case-Control Studie In vitro studie Human Hearing loss In silico Presbycusi Nerve Tissue Proteins Computational biology Protein Serine-Threonine Kinases Polymorphism Single Nucleotide 03 medical and health sciences Audiometry Hair Cells Auditory Genetics medicine Animals Humans Genetic Predisposition to Disease Gene Allele frequency gene expression protein modelling Aged Whole Genome Sequencing Animal Gene Expression Profiling Membrane Transport Proteins biology.organism_classification Protocadherins HEK293 Cells 030104 developmental biology Intracellular Signaling Peptides and Protein Case-Control Studies Mutation Nerve Tissue Protein Cadherin Gene expression Cohort Studie |
| Zdroj: | Gene. 742:144561 |
| ISSN: | 0378-1119 |
| DOI: | 10.1016/j.gene.2020.144561 |
| Popis: | Age-related hearing loss (ARHL) is the most frequent sensory disorder in the elderly, affecting approximately one-third of people aged more than 65 years. Despite a large number of people affected, ARHL is still an area of unmet clinical needs, and only a few ARHL susceptibility genes have been detected so far. In order to further investigate the genetics of ARHL, we analyzed a series of 46 ARHL candidate genes, selected according to previous Genome Wide Association Studies (GWAS) data, literature updates and animal models, in a large cohort of 464 Italian ARHL patients. We have filtered the variants according to a) pathogenicity prediction, b) allele frequency in public databases, c) allele frequency in an internal cohort of 113 healthy matched controls, and 81 healthy semi-supercentenarians. After data analysis, all the variants of interest have been tested by functional “in silico” or “in vitro” experiments (i.e., molecular dynamics simulations and protein translation analysis) to assess their pathogenic role, and the expression of the mutated genes have been checked in mouse or zebrafish inner ear. This multi-step approach led to the characterization of a series of ultra-rare likely pathogenic variants in DCLK1, SLC28A3, CEP104, and PCDH20 genes, contributing to describe the first association of these genes with ARHL in humans. These results provide essential insights on the understanding of the molecular bases of such a complex, heterogeneous and frequent disorder, unveiling new possible targets for the future development of innovative therapeutic and preventive approaches that could improve the quality of life of the millions of people affected worldwide. |
| Databáze: | OpenAIRE |
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