Clinical Application of Screening for GJB2 Mutations before Cochlear Implantation in a Heterogeneous Population with High Rate of Autosomal Recessive Nonsyndromic Hearing Loss

Clinical application of mutation screening and its effect on the outcome of cochlear implantation is widely debated. We investigated the effect of mutations in GJB2 gene on the outcome of cochlear implantation in a population with a high rate of consanguineous marriage and autosomal recessive nonsyndromic hearing loss. Two hundred and one children with profound prelingual sensorineural hearing loss were included. Forty-six patients had 35delG in GJB2. Speech awareness thresholds (SATs) and speech recognition thresholds (SRTs) improved following implantation, but there was no difference in performance between patients with GJB2-related deafness versus control (all P > 0.10). Both groups had produced their first comprehensible words within the same period of time following implantation (2.27 months in GJB2-related deaf versus 2.62 months in controls, P = 0.22). Although our findings demonstrate the need to uncover unidentified genetic causes of hereditary deafness, they do not support the current policy for genetic screening before cochlear implantation, nor prove a prognostic value

Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss

Mutations in GJB2 , encoding connexin 26 (Cx26), cause both autosomal dominant and autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNA3 and DFNB1 loci, respectively. Most of the over 100 described GJB2 mutations cause ARNSHL. Only a minority has been associated with autosomal dominant hearing loss. In this study, we present two families with autosomal dominant nonsyndromic hearing loss caused by a novel mutation in GJB2 (p.Asp46Asn). Both families were ascertained from the same village in northern Iran consistent with a founder effect. This finding implicates the D46N missense mutation in Cx26 as a common cause of deafness in this part of Iran mandating mutation screening of GJB2 for D46N in all persons with hearing loss who originate from this geographic region. © 2011 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83755/1/33209_ftp.pd

Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants

Q1Q1Artículo original445-453Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) >0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness

Association Between Interleukin 16 Gene Polymorphisms (rs1131445, rs4072111) and Late Onset of Alzheimer’s Disease in Iranian Patients

Objectives: Alzheimer’s disease is the most common kind of dementia in the old age, and its incidence increases with age. Previous studies have shown that cytokines are proteins that play an important role in inflammation, and their level changes in inflammatory diseases. Since Alzheimer’s disease is an inflammatory disease, cytokines may influence the occurrence of this disease. IL16 is a cytokine whose role has been proved in many inflammatory diseases. This gene is one of the coding genes of cytokines of the inflammatory process. It may be responsible for inflammatory pathology seen around old age plaques in Alzheimer’s disease. It can also associate with the pathology of Alzheimer’s disease. Therefore, the aim of this study was to investigate the effects of 2 polymorphisms of gene IL16 (rs1131445 and rs4072111) on the risk of patients diagnosed with Alzheimer’s disease in the Iranian population. Methods & Materials: In this study, the intervention group consisted of 144 individuals who were diagnosed with Alzheimer’s disease by psychologists based on a clinical test (DSM-IV), and the control group included 173 healthy individuals with no psychological disorders. DNA was extracted by salting out technique. The PCR response was conducted (for replicating the mentioned pieces) for any polymorphism in optimized conditions by using designed primers. The product of PCR was first checked for the confirmation of accurate function of PCR using polyacrylamide gel electrophoresis (PAGE). Next, the PCR product was dissected by restriction fragment length polymorphism (RFLP) method with intended confining enzyme, and then the genotype of the samples was determined by PAGE. Individual genotypes were determined using the PCR-RFLP method. Statistical analyses were done using OpenEpi 2.3.1 and SPSS 11.5. Results: The study of allelic analysis between the control and intervention groups by considering the confidence interval (CI=90%) and significant level (0.05) for rs1131445 showed that the C allele had no significant association with Alzheimer’s disease (P=0.656). The TC genotype did not show any significant difference with TT genotype (P=0.614). However, the study of allelic analysis for rs4072111 polymorphism between 2 groups showed that the relationship of T allele with the disease is significant, and this allele has a protective role in creating the disease (P=0.008). In addition, TC genotype as a protective status showed a significant association with Alzheimer’s disease (P=0.007). Conclusion: The existence of polymorphism in some genes of the inflammatory pathway could make people susceptible to Alzheimer’s disease. The genetic changes in DNA sequence of gene IL16 could result in changes in cytokine product or its function. The association between rs4072111 and Alzheimer’s disease supports the presumptions and shows a probable role of this polymorphism in Alzheimer disease. Besides, the association between rs1131445 and Alzheimer disease cannot be proven due to the small number of samples (Power: 8.23%)

Effects of Herbal Compound (IMOD) on Behavior and Expression of Alzheimer's Disease Related Genes in Streptozotocin-Rat Model of Sporadic Alzheimer’s Disease

Purpose: Sporadic Alzheimer’s disease (AD) accounts for over 95% of cases. Possible mechanisms of AD such as inflammation and oxidative stresses in the brain motivate researchers to follow many therapies which would be effective, especially in the early stages of the disease. IMOD, the herbal extract of R. Canina, T. Vulgare and U. Dioica plant species enriched with selenium, has anti-inflammatory, immunoregulatory and protective effects against oxidative stress. Methods: In this study three AD-related genes, DAXX, NFκβ and VEGF, were chosen as candidate to investigate the neuroprotective effect of the extract by comparing their expression levels in the hippocampus of rat model of sporadic AD, using qPCR in the herbal-treated and control groups. The therapeutic effects on learning and memory levels were evaluated by Morris Water Maze (MWM) test. Results: Gene expression results were indicative of significant up-regulation of Vegf in rat’s hippocampus after treatment with the herbal extract comparing to model group (P-value= 0.001). The MWM results showed significant changes in path length and time for finding the hidden platform in all groups during test and the same change in the treated comparing to the control group in memory level. Conclusion: It could be concluded that the herbal extract may have significant effect on gene expression but not on behavioral level

Effects of Ectoine on Behavior and Candidate Genes Expression in ICV-STZ Rat Model of Sporadic Alzheimer’s Disease

Purpose: Alzheimer’s disease (AD) is pathologically defined by the presence of amyloid plaques and tangles in the brain, therefore, any drug or compound with potential effect on lowering amyloid plaques, could be noticed for AD management especially in the primary phases of the disease. Ectoine constitutes a group of small molecule chaperones (SMCs). SMCs inhibit proteins and other changeable macromolecular structures misfolding from environmental stresses. Ectoine has been reported successfully prohibit insulin amyloid formation in vitro. Methods: We selected eight genes, DAXX, NFκβ, VEGF, PSEN1, MTAP2, SYP, MAPK3 and TNFα genes which had previously showed significant differential expression in Alzheimer human brain and STZ- rat model. We considered the neuroprotective efficacy by comparing the expression of candidate genes levels in the hippocampus of rat model of Sopradic Alzheimer’s disease (SAD), using qPCR in compound-treated and control groups as well as therapeutic effects at learning and memory levels by using Morris Water Maze (MWM) test. Results: Our results showed significant down-regulation of Syp, Mapk3 and Tnfα and up-regulation of Vegf in rat’s hippocampus after treatment with ectoine comparing to the STZ-induced group. In MWM, there was no significant change in swimming distance and time for finding the hidden platform in treated comparing to STZ-induced group. In addition, it wasn’t seen significant change in compound-treated comparing to STZ-induced and control groups in memory level. Conclusion: It seems this compound may have significant effect on expression level of some AD- related genes but not on clinical levels