Frequency of c.35delG Mutation in GJB2 Gene (Connexin 26) in Syrian Patients with Nonsyndromic Hearing Impairment

Abstract

Background Hearing impairments (HI) are the most common birth defect worldwide. Very large numbers of genes have been identified but the most profound is GJB2. The clinical interest regarding this gene is very pronounced due to its high carrier frequency (0.5–5.4%) across different ethnic groups. This study aimed to determine the prevalence of common GJB2 mutations in Syrian patients with profound sensorineural HI. Methods We carried out PCR, restriction enzyme based screening, and sequencing of 132 Syrian patients diagnosed clinically with hereditary deafness for different GJB2 mutations. Results The result revealed that, in GJB2 gene, c.35delG is the most prevalent among affected studied subjects (13.64%), followed by c.457G>A (2.4%). Conclusion The benefit of this study on the one hand is its first report of prelingual deafness causative gene mutations identified by sequencing technology in the Syrian families. It is obvious from the results that the deployment in biomedical research is highly effective and has a great impact on the ability to uncover the cause of genetic variation in different genetic diseases.

Hearing Phenotypes of Patients with Hearing Loss Homozygous for the GJB2 c.235delc Mutation

“…Currently, more than 300 mutations in GJB2 have been reported (the Human Gene Mutation Database) [ 25 ]. Notably, several alleles have been found to be particularly enriched in certain populations: c.35delG in Europe, America, North Africa, and the Middle East; c.71G>A in India and Pakistan; c.167delT in Ashkenazi Jews; and c.109G>A in East and Southeast Asia [ 16 , 26 – 28 ]. The contribution of GJB2 mutations to genetic HL varies by ethnicity, but such mutations are the primary cause of congenital severe-to-profound autosomal recessive NSHL (up to 50% worldwide) [ 29 , 30 ].…”

A Chemical Chaperone Restores Connexin 26 Mutant Activity

“…To date, >100 different Cx26 mutations have been described, with new variants being continually discovered. − Different genetic disorders or variants produce varying phenotypes. − For example, the truncated variant 35delG induces the complete loss of the connexin function, , whereas, in the presence of the M1V, P173R, and R184P mutations, Cx26 protein is not produced. , Furthermore, connexins with M34T, L90P, R127H, or F161S do not function or are not correctly transported and incorporated into the cell membrane despite their high expression levels. , There are two possible effects of Cx26 mutations: the misfolding and removal of the protein or its incorporation into the plasma membrane in the inactive form. − Similar phenomena were described in cystic fibrosis transmembrane conductance regulator (CFTR), and other proteins have been developed to restore those functionalities. − The functional hemichannel properties of wild-type (WT) Cx26 have been characterized via voltage clamp experiments, single-channel analyses, molecular dynamic analyses, Raman measurements, and cell-based microarray experiments. − Studies have reported that Cx26 mutations affect its hemichannel activity and are thermosensitive. , In a previous study, we used HeLa cells as an expression system for WT Cx26 and its mutated forms to investigate the channel function of WT Cx26 and mutants R127H, R184P, and F161S …”

“…16−19 Different genetic disorders or variants produce varying phenotypes. 18−20 For example, the truncated variant 35delG induces the complete loss of the connexin function, 21,22 whereas, in the presence of the M1V, P173R, and R184P mutations, Cx26 protein is not produced. 9,23 Furthermore, connexins with M34T, L90P, R127H, or F161S do not function or are not correctly transported and incorporated into the cell membrane despite their high expression levels.…”

<i>GJB2</i> Gene Related Nonsyndromic Hearing Loss in Mazandaran Province, North of Iran

“…[12] [13] [14].The type and prevalence of mutations vary in different populations. The frequency of GJB2 mutations is reported from different provinces in Iran.…”