Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway.

Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed Gjb2+/- mice as a model of heterozygous human carriers of 35delG. Compared to control mice, auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) worsened over time more rapidly in Gjb2+/- mice, indicating they were affected by accelerated age-related hearing loss (ARHL), or presbycusis. We linked causally the auditory phenotype of Gjb2+/- mice to apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, decreased nutrient delivery to the sensory epithelium via cochlear gap junctions and deregulated expression of genes that are under transcriptional control of the nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal regulator of tolerance to redox stress. Moreover, a statistically significant genome-wide association with two genes (PRKCE and TGFB1) related to the Nrf2 pathway (p-value < 4â€¯× 10-2) was detected in a very large cohort of 4091 individuals, originating from Europe, Caucasus and Central Asia, with hearing phenotype (including 1076 presbycusis patients and 1290 healthy matched controls). We conclude that (i) elements of the Nrf2 pathway are essential for hearing maintenance and (ii) their dysfunction may play an important role in the etiopathogenesis of human presbycusis.

NeuroArray, A Custom CGH Microarray to Decipher Copy Number Variants in Alzheimer's Disease.

BACKGROUND: Copy Number Variants (CNVs) represent a prevailing type of structural variation (deletions or duplications) in the human genome. In the last few years, several studies have demonstrated that CNVs represent significant mutations in Alzheimer's Disease (AD) hereditability. Currently, innovative high-throughput platforms and bioinformatics algorithms are spreading to screening CNVs involved in different neurological diseases. In particular, the use of custom arrays, based on libraries of probes that can detect significant genomic regions, have greatly improved the resolution of targeted regions and the identification of chromosomal aberrations. OBJECTIVE: In this work, we report the use of NeuroArray, a custom CGH microarray useful to screening and further investigate the role of the recurring genomic aberrations in patients with confirmed or suspected AD. METHODS: The custom oligonucleotide aCGH design includes 641 genes and 9118 exons, linked to AD. The genomic DNA was isolated from blood samples of AD affected patients. The entire protocol of custom NeuroArray included digestion, labelling and hybridization steps as a standard aCGH assay. RESULTS: The NeuroArray analysis revealed the presence of amplifications in several genes associated with AD. In the coding regions of these genes, 14,586 probes were designed with a 348 bp median probe spacing. The majority of targeted AD genes map on chromosomes 1 and 10. A significant aspect of the NeuroArray design is that 95% of the total exon targets is covered by at least one probe, a resolution higher than CGH array platforms commercially available. CONCLUSION: By identifying with a high sensitivity the chromosomal abnormalities in a large panel of AD-related genes and other neurological diseases, the NeuroArray platform is a valid tool for clinical diagnosis.

Copy Number Variants in Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating disease mainly afflicting elderly people, characterized by decreased cognition, loss of memory, and eventually death. Although risk and deterministic genes are known, major genetics research programs are underway to gain further insights into the inheritance of AD. In the last years, in particular, new developments in genome-wide scanning methodologies have enabled the association of a number of previously uncharacterized copy number variants (CNVs, gain or loss of DNA) in AD. Because of the exceedingly large number of studies performed, it has become difficult for geneticists as well as clinicians to systematically follow, evaluate, and interpret the growing number of (sometime conflicting) CNVs implicated in AD. In this review, after a brief introduction of this type of structural variation, and a description of available databases, computational analyses, and technologies involved, we provide a systematic review of all published data showing statistical and scientific significance of pathogenic CNVs and discuss the role they might play in AD.