PUBLICATION
New age-related hearing loss candidate genes in humans: an ongoing challenge
- Authors
- Di Stazio, M., Morgan, A., Brumat, M., Bassani, S., Dell'Orco, D., Marino, V., Garagnani, P., Giuliani, C., Gasparini, P., Girotto, G.
- ID
- ZDB-PUB-200403-79
- Date
- 2020
- Source
- Gene 742: 144561 (Journal)
- Registered Authors
- Keywords
- Age-related hearing loss gene discovery, Gene expression, In vitro studies, Protein modelling
- MeSH Terms
-
- Aged
- Aged, 80 and over
- Animals
- Audiometry
- Cadherins/genetics
- Cadherins/metabolism
- Case-Control Studies
- Cell Cycle Proteins/genetics
- Cell Cycle Proteins/metabolism
- Cohort Studies
- Female
- Gene Expression Profiling
- Genetic Predisposition to Disease*
- HEK293 Cells
- Hair Cells, Auditory/pathology*
- Humans
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Italy
- Male
- Membrane Transport Proteins/genetics
- Membrane Transport Proteins/metabolism
- Mice
- Middle Aged
- Models, Animal
- Mutation
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism
- Polymorphism, Single Nucleotide
- Presbycusis/diagnosis
- Presbycusis/genetics*
- Presbycusis/pathology
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism
- Severity of Illness Index
- Whole Genome Sequencing
- Zebrafish
- PubMed
- 32173538 Full text @ Gene
Citation
Di Stazio, M., Morgan, A., Brumat, M., Bassani, S., Dell'Orco, D., Marino, V., Garagnani, P., Giuliani, C., Gasparini, P., Girotto, G. (2020) New age-related hearing loss candidate genes in humans: an ongoing challenge. Gene. 742:144561.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping