Molecular pathology of 6 novel GJB2 allelic variants detected in familial and sporadic Iranian non syndromic hearing loss cases

Background: Mutations of GJB2 gene encoding connexion 26 are the most common cause of hearing loss in many populations. A very wide spectrum of GJB2 gene mutations associated with hearing loss have been detected but pathogenic role has been tested only for a part of them. In this study, we have provided genetic evidence on the pathogenicity of our previously reported novel GJB2 allelic variants. Methods: The pathogenic role of GJB2 allelic variants were assessed using co segregation of each allelic variant with hearing loss in family members, absence of the allelic variants in control populations, coexistence with a second GJB2 mutation, nature of the amino acid substitution and evolutionary conservation of the appropriate amino acid. Results: The GJB2 allelic variants including 363delC, 327delGGinsA, H16R and G200R have been co segregated with autosomal recessive non syndromic hearing loss in five families and are not found in control subjects. The G130V and K102Q were found in heterozygous state in two deaf individuals. G130V results in an exchange a residue highly conserved among all the connexins but was found with a rate of 1% in control subjects and K102Q results in an exchange a residue not conserved among all the connexins and not identified in control subjects. Conclusion: We conclude that, 363delC, 327delGGinsA, H16R and G200R may be pathogenic. However, the pathogenicity and inheritance of K102Q and G130V can not be assessed clearly and remains to be identified

High carrier frequency of the GJB2 mutation (35delG) in the north of Iran

Objective: Mutations in the GJB2 gene are a major cause of autosomal recessive and sporadic non-syndromic hearing loss in many populations. A single mutation of this gene (35delG) accounts for approximately 70% of mutations in Caucasians with a carrier frequency of 2-4% in Europe. This study aims to determine the rate of 35delG carrier frequency in Iran. Methods: Genomic DNA was extracted from a total of 550 unaffected unrelated subjects from 4 provinces of Iran following the standard phenol chloroform procedure. The one base pair deletion (35delG) was analysed using a nested PCR procedure; 35delG mutation carriers were subsequently confirmed by sequence analysis. Moreover, using the Binomial probability distribution, we compared the 35delG carrier frequency of Iranian population with the various Middle Eastern and overall European populations. Results: Of the four populations studied, we found a high carrier frequency of 2.8% in Gilan province in the north of Iran. The overall 35delG carrier frequency was found to be 1.25% in the populations studied (our present and previous data) which is similar to the overall 35delG carrier frequency detected in Middle Eastern populations, but Significantly tower than that identified in European populations. (c) 2007 Elsevier Ireland Ltd. All rights reserved

Can environmental or occupational hazards alter the sex ratio at birth? A systematic review

More than 100 studies have examined whether environmental or occupational exposures of parents affect the sex ratio of their offspring at birth. For this review, we searched Medline and Web of Science using the terms ‘sex ratio at birth’ and ‘sex ratio and exposure’ for all dates, and reviewed bibliographies of relevant studies to find additional articles. This review focuses on exposures that have been the subject of at least four studies including polychlorinated biphenyls (PCBs), dioxins, pesticides, lead and other metals, radiation, boron, and g-forces. For paternal exposures, only dioxins and PCBs were consistently associated with sex ratios higher or lower than the expected 1.06. Dioxins were associated with a decreased proportion of male births, whereas PCBs were associated with an increased proportion of male births. There was limited evidence for a decrease in the proportion of male births after paternal exposure to DBCP, lead, methylmercury, non-ionizing radiation, ionizing radiation treatment for childhood cancer, boron, or g-forces. Few studies have found higher or lower sex ratios associated with maternal exposures. Studies in humans and animals have found a reduction in the number of male births associated with lower male fertility, but the mechanism by which environmental hazards might change the sex ratio has not yet been established

Case Reports - Presentation Of A Pedigree Of An Iranian Family With Two Members With Cutis Laxaautosomal Recessive Type I

Congenital cutis laxa is an exceptional condition. No large scale pedigree has been reported from Iran. We report a family with 106 members with two members affected with cutis laxa. Our cases were two patients (male and female) with pre- and postnatal growth retardation, cutis laxa, characteristic facies and other manifestations which proved that they were affected with cutis laxa. Their family history was studied and a large pedigree was drawn up. Based on the findings in their pedigree pattern, in addition to clinical and pathological studies, one can say that cutis laxa in this family is autosomal recessive. We also showed obligate carrier members in the family. Recent studies have shown that cutis laxa is a heterogeneous group of conditions both clinically and genetically.Autosomal dominant, autosomal recessive, X-linked and also acquired forms have been reported. Our study indicates that our case is an autosomal recessive type I. We discussed the pedigree that covers five generations

Systems biomedicine of rabies delineates the affected signaling pathways

The prototypical neurotropic virus, rabies, is a member of the Rhabdoviridae family that causes lethal encephalomyelitis. Although there have been a plethora of studies investigating the etiological mechanism of the rabies virus and many precautionary methods have been implemented to avert the disease outbreak over the last century, the disease has surprisingly no definite remedy at its late stages. The psychological symptoms and the underlying etiology, as well as the rare survival rate from rabies encephalitis, has still remained a mystery. We, therefore, undertook a systems biomedicine approach to identify the network of gene products implicated in rabies. This was done by meta-analyzing whole-transcriptome microarray datasets of the CNS infected by strain CVS-11, and integrating them with interactome data using computational and statistical methods. We first determined the differentially expressed genes (DEGs) in each study and horizontally integrated the results at the mRNA and microRNA levels separately. A total of 61 seed genes involved in signal propagation system were obtained by means of unifying mRNA and microRNA detected integrated DEGs. We then reconstructed a refined protein–protein interaction network (PPIN) of infected cells to elucidate the rabies-implicated signal transduction network (RISN). To validate our findings, we confirmed differential expression of randomly selected genes in the network using Real-time PCR. In conclusion, the identification of seed genes and their network neighborhood within the refined PPIN can be useful for demonstrating signaling pathways including interferon circumvent, toward proliferation and survival, and neuropathological clue, explaining the intricate underlying molecular neuropathology of rabies infection and thus rendered a molecular framework for predicting potential drug targets

Systems biomedicine of rabies delineates the affected signaling pathways

The prototypical neurotropic virus, rabies, is a member of the Rhabdoviridae family that causes lethal encephalomyelitis. Although there have been a plethora of studies investigating the etiological mechanism of the rabies virus and many precautionary methods have been implemented to avert the disease outbreak over the last century, the disease has surprisingly no definite remedy at its late stages. The psychological symptoms and the underlying etiology, as well as the rare survival rate from rabies encephalitis, has still remained a mystery. We, therefore, undertook a systems biomedicine approach to identify the network of gene products implicated in rabies. This was done by meta-analyzing whole-transcriptome microarray datasets of the CNS infected by strain CVS-11, and integrating them with interactome data using computational and statistical methods. We first determined the differentially expressed genes (DEGs) in each study and horizontally integrated the results at the mRNA and microRNA levels separately. A total of 61 seed genes involved in signal propagation system were obtained by means of unifying mRNA and microRNA detected integrated DEGs. We then reconstructed a refined protein–protein interaction network (PPIN) of infected cells to elucidate the rabies-implicated signal transduction network (RISN). To validate our findings, we confirmed differential expression of randomly selected genes in the network using Real-time PCR. In conclusion, the identification of seed genes and their network neighborhood within the refined PPIN can be useful for demonstrating signaling pathways including interferon circumvent, toward proliferation and survival, and neuropathological clue, explaining the intricate underlying molecular neuropathology of rabies infection and thus rendered a molecular framework for predicting potential drug targets

"Frequency of A Very Rare 35delG Mutation in Two Ethnic Groups of Iranian Populations "

The 35delG mutation in the Connexin 26 gene (Cx26), at the DNFB1 locus is the most common mutation in the patients with autosomal recessive non-syndromic hearing loss (ARNSHL). We have studied a total of 224 deaf cases from 189 families in two populations of Iran (Sistan va Bluchestan and Hormozgan provinces) by prescreening nested PCR, polyacrylamide gel electrophoresis and consequent direct sequencing method for all cases. The aim of the present work was to find prevalence of GJB2 mutations in the populations studied. Four different GJB2 mutations including 35delG, W24X, R127H and (V27I + E114 G) were identified in 11 of 189 families (5.8%). Two polymorphisms (V27I and V153I) also were detected in 14 families. A polymorphism S86T was determined in all cases. Homozygote 35delG mutation was found only in 1 of 189 families (0.5%).The rate of Cx26 mutations found in this study was lower than other Iranian populations. So the cause of deafness in the populations studied remains to be detected in other loci or genes

Autosomal Recessive and Sporadic Non Syndromic Hearing Loss and the Incidence of Cx26 Mutations in a Province of Iran

Despite the enormous heterogeneity of genetic hearing loss, mutations in the GJB2 (connexin 26) gene located on “DFNB1” locus (13q12) account for up to 50% of cases of autosomal recessive non-syndromic hearing loss (ARNSHL) in some populations. This study describes the analysis of 100 autosomal recessive and sporadic nonsyndromic hearing loss individuals from 79 families each having at least one deaf child in Chehar Mahal va Bakhtiari province in west of Iran. We have investigated the prevalence of the connexin 26 gene mutations using nested PCR strategy to screen the predominant 35delG mutation and subsequent direct sequencing to detect other Cx26 mutations. Seven different genetic variants were detected from which one novel variant was including 363delC. The 35delG was the most common mutation found in 5 of 79 families (6.3%). Cx26 related deafness mutations (35delG, [V27I; E114G]) and R127H) were found in 12 of 158 chromosomes studied (7.8%). We conclude that the association of Cx26 mutations with deafness in Chehar Mahal va Bakhtiari province is low and looks like most other populations of Iran