scholarly journals High Rates of Three Common GJB2 Mutations c.516G>C, c.-23+1G>A, c.235delC in Deaf Patients from Southern Siberia Are Due to the Founder Effect

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 833 ◽  
Author(s):  
Marina V. Zytsar ◽  
Marita S. Bady-Khoo ◽  
Valeriia Yu. Danilchenko ◽  
Ekaterina A. Maslova ◽  
Nikolay A. Barashkov ◽  
...  
Keyword(s):  
Founder Effect ◽  
Transmembrane Protein ◽  
Indigenous Populations ◽  
Gjb2 Gene ◽  
Southern Siberia ◽  
C 23 ◽  
High Prevalence ◽  
Ethnic History ◽  
Single Marker ◽  
Gjb2 Mutations

The mutations in the GJB2 gene (13q12.11, MIM 121011) encoding transmembrane protein connexin 26 (Cx26) account for a significant portion of hereditary hearing loss worldwide. Earlier we found a high prevalence of recessive GJB2 mutations c.516G>C, c.-23+1G>A, c.235delC in indigenous Turkic-speaking Siberian peoples (Tuvinians and Altaians) from the Tyva Republic and Altai Republic (Southern Siberia, Russia) and proposed the founder effect as a cause for their high rates in these populations. To reconstruct the haplotypes associated with each of these mutations, the genotyping of polymorphic genetic markers both within and flanking the GJB2 gene was performed in 28 unrelated individuals homozygous for c.516G>C (n = 18), c.-23+1G>A (n = 6), or c.235delC (n = 4) as well as in the ethnically matched controls (62 Tuvinians and 55 Altaians) without these mutations. The common haplotypes specific for mutations c.516G>C, c.-23+1G>A, or c.235delC were revealed implying a single origin of each of these mutations. The age of mutations estimated by the DMLE+ v2.3 software and the single marker method is discussed in relation to ethnic history of Tuvinians and Altaians. The data obtained in this study support a crucial role of the founder effect in the high prevalence of GJB2 mutations c.516G>C, c.-23+1G>A, c.235delC in indigenous populations of Southern Siberia.

A common founder effect of the splice site variant c.-23 + 1G > A in GJB2 gene causing autosomal recessive deafness 1A (DFNB1A) in Eurasia

2021 ◽  
Author(s):  
Aisen V. Solovyev ◽  
Alena Kushniarevich ◽  
Elena Bliznetz ◽  
Marita Bady-Khoo ◽  
Maria R. Lalayants ◽  
...  
Keyword(s):  
Splice Site ◽  
Founder Effect ◽  
Autosomal Recessive ◽  
Gjb2 Gene ◽  
C 23 ◽  
Common Founder ◽  
Splice Site Variant

scholarly journals A Common Founder Effect of the Splice Site Variant c.-23+1G>A in GJB2 Gene Causing Autosomal Recessive Deafness 1A (DFNB1A) in Eurasia

2021 ◽  
Author(s):  
Aisen V Solovyev ◽  
Alena Kushniarevich ◽  
Elena Bliznetz ◽  
Marita Bady-Khoo ◽  
Maria R Lalayants ◽  
...  
Keyword(s):  
Splice Site ◽  
Founder Effect ◽  
Autosomal Recessive ◽  
Gjb2 Gene ◽  
Published Data ◽  
Migration Routes ◽  
C 23 ◽  
The World ◽  
Common Founder ◽  
Splice Site Variant

Abstract The mutations in the GJB2 gene are known to be a major cause of autosomal recessive deafness 1A (OMIM 220290). The most common pathogenic variants of the GJB2 gene have high ethno-geographic specificity in their distribution that being attributed to a founder effect related with Neolithic migration routes of Homo sapiens. Curiously, the c.-23+1G>A splice site variant is frequently found among deaf patients of both Caucasian and Asian origin. It is currently unknown whether this mutation did spread across Eurasia as a result of the founder effect or it could have multiple local centers of origin. To determine the origin of the c.-23+1G>A we reconstructed 𝑓2-haplotypes by genotyping SNPs on the Illumina OmniExpress 730K platform in 23 deaf individuals homozygous for this variant from different populations of Eurasia (Yakuts, Tuvinians, Evenk, Kumyk, Armenian, Russians and Slovak). The analysis revealed that the homozygosity regions in different individuals overlapped in one short region with the length of ~5.2 kb. These data support the hypothesis of the common founder effect in distribution of the c.-23+1G>A variant of GJB2 gene. Based on the published data on the c.-23+1G>A prevalence among 16,177 deaf people and calculation of TMRCA of the 𝑓2-haplotypes carrying this variant we reconstructed the potential migration routes of the c.-23+1G>A carriers around the world. This analysis indicates that the c.-23+1G>A variant may have originated approximately 6,000 years ago in the territory of the Caucasus or Middle East, followed by spread throughout Europe, South and Central Asia and other regions of the world.

scholarly journals Unique Mutational Spectrum of the GJB2 Gene and Its Pathogenic Contribution to Deafness in Tuvinians (Southern Siberia, Russia): A High Prevalence of Rare Variant c.516G>C (p.Trp172Cys)

Genes ◽  
2019 ◽  
Vol 10 (6) ◽  
pp. 429 ◽  
Author(s):  
Olga L. Posukh ◽  
Marina V. Zytsar ◽  
Marita S. Bady-Khoo ◽  
Valeria Yu. Danilchenko ◽  
Ekaterina A. Maslova ◽  
...  
Keyword(s):  
Rare Variant ◽  
Gjb2 Gene ◽  
Exon 2 ◽  
Southern Siberia ◽  
Mutational Spectrum ◽  
Recessive Mutations ◽  
High Prevalence ◽  
Sporadic Cases ◽  
Different Populations ◽  
Tyva Republic

Mutations in the GJB2 gene are the main cause for nonsyndromic autosomal recessive deafness 1A (DFNB1A) in many populations. GJB2 mutational spectrum and pathogenic contribution are widely varying in different populations. Significant efforts have been made worldwide to define DFNB1A molecular epidemiology, but this issue still remains open for some populations. The main aim of study is to estimate the DFNB1A prevalence and GJB2 mutational spectrum in Tuvinians—an indigenous population of the Tyva Republic (Southern Siberia, Russia). Sanger sequencing was applied to analysis of coding (exon 2) and non-coding regions of GJB2 in a cohort of Tuvinian patients with hearing impairments (n = 220) and ethnically matched controls (n = 157). Diagnosis of DFNB1A was established for 22.3% patients (28.8% of familial vs 18.6% of sporadic cases). Our results support that patients with monoallelic GJB2 mutations (8.2%) are coincidental carriers. Recessive mutations p.Trp172Cys, c.-23+1G>A, c.235delC, c.299_300delAT, p.Val37Ile and several benign variants were found in examined patients. A striking finding was a high prevalence of rare variant p.Trp172Cys (c.516G>C) in Tuvinians accounting for 62.9% of all mutant GJB2 alleles and a carrier frequency of 3.8% in controls. All obtained data provide important targeted information for genetic counseling of affected Tuvinian families and enrich current information on variability of GJB2 worldwide.

scholarly journals Haplotype Analysis of GJB2 Mutations: Founder Effect or Mutational Hot Spot?

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 250 ◽  
Author(s):  
Jun Shinagawa ◽  
Hideaki Moteki ◽  
Shin-ya Nishio ◽  
Yoshihiro Noguchi ◽  
Shin-ichi Usami
Keyword(s):  
Hearing Loss ◽  
Founder Effect ◽  
Hot Spot ◽  
Distribution Patterns ◽  
Gjb2 Gene ◽  
Founder Effects ◽  
Haplotype Data ◽  
Clock Analysis ◽  
Specific Haplotype ◽  
Gjb2 Mutations

The GJB2 gene is the most frequent cause of congenital or early onset hearing loss worldwide. In this study, we investigated the haplotypes of six GJB2 mutations frequently observed in Japanese hearing loss patients (i.e., c.235delC, p.V37I, p.[G45E; Y136X], p.R143W, c.176_191del, and c.299_300delAT) and analyzed whether the recurring mechanisms for each mutation are due to founder effects or mutational hot spots. Furthermore, regarding the mutations considered to be caused by founder effects, we also calculated the age at which each mutation occurred using the principle of genetic clock analysis. As a result, all six mutations were observed in a specific haplotype and were estimated to derive from founder effects. Our haplotype data together with their distribution patterns indicated that p.R143W and p.V37I may have occurred as multiple events, and suggested that both a founder effect and hot spot may be involved in some mutations. With regard to the founders’ age of frequent GJB2 mutations, each mutation may have occurred at a different time, with the oldest, p.V37I, considered to have occurred around 14,500 years ago, and the most recent, c.176_191del, considered to have occurred around 4000 years ago.

scholarly journals Functional Evaluation of a Rare Variant c.516G>C (p.Trp172Cys) in the GJB2 (Connexin 26) Gene Associated with Nonsyndromic Hearing Loss

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 61
Author(s):  
Ekaterina A. Maslova ◽  
Konstantin E. Orishchenko ◽  
Olga L. Posukh
Keyword(s):  
Hearing Loss ◽  
Transmembrane Protein ◽  
Amino Acid Position ◽  
Indigenous Populations ◽  
Gjb2 Gene ◽  
Connexin 26 ◽  
Functional Evaluation ◽  
Nonsyndromic Hearing Loss ◽  
Extracellular Loop ◽  
Gene Encoding

Mutations in the GJB2 gene encoding transmembrane protein connexin 26 (Cx26) are the most common cause for hearing loss worldwide. Cx26 plays a crucial role in the ionic and metabolic homeostasis in the inner ear, indispensable for normal hearing process. Different pathogenic mutations in the GJB2 gene can affect all stages of the Cx26 life cycle and result in nonsyndromic autosomal recessive (DFNB1) or dominant (DFNA3) deafness and syndromes associating hearing loss with skin disorders. This study aims to elucidate the functional consequences of a rare GJB2 variant c.516G>C (p.Trp172Cys) found with high frequency in deaf patients from indigenous populations of Southern Siberia (Russia). The substitution c.516G>C leads to the replacement of tryptophan at a conserved amino acid position 172 with cysteine (p.Trp172Cys) in the second extracellular loop of Cx26 protein. We analyzed the subcellular localization of mutant Cx26-p.Trp172Cys protein by immunocytochemistry and the hemichannels permeability by dye loading assay. The GJB2 knockout HeLa cell line has been generated using CRISPR/Cas9 genome editing tool. Subsequently, the HeLa transgenic cell lines stably expressing different GJB2 variants (wild type and mutations associated with hearing loss) were established based on knockout cells and used for comparative functional analysis. The impaired trafficking of mutant Cx26-p.Trp172Cys protein to the plasma membrane and reduced hemichannels permeability support the pathogenic effect of the c.516G>C (p.Trp172Cys) variant and its association with nonsyndromic hearing loss. Our data contribute to a better understanding of the role of mutations in the second extracellular loop of Cx26 protein in pathogenesis of deafness.

scholarly journals A review of the reasons for high prevalence and rapid progression of COVID-19 in men

2021 ◽  
Vol 7 (1) ◽  
pp. e03-e03
Author(s):  
Neda Taghizabet ◽  
Fatemeh Rezaei-Tazangi ◽  
Hossein Roghani‐Shahraki
Keyword(s):  
Transmembrane Protein ◽  
Rapid Progression ◽  
Acute Type ◽  
Converting Enzyme ◽  
Immune Functions ◽  
Male And Female ◽  
Angiotensin Converting Enzyme 2 ◽  
High Prevalence ◽  
Hormonal Levels

Previous studies have demonstrated a relationship between gender and COVID-19 outcomes. In addition, this is confirmed that men have more danger of progressing an acute type of the illness than women, specifies the significance of miscellaneous data related to male and female patients with COVID-19. In other words, some factors like hormonal levels and immune function may interact with each other. A perception of the fundamental reasons for gender diversities in COVID-19 patients can beget a chance for disease prevention and faster treatment. The present study evaluates the role of gender in the incidence and progression of the COVID-19 disease. It has been explained that how gender affects angiotensin-converting enzyme 2 (ACE2), which is a basic factor for the COVID-19 pathogenesis introducing the sex diversities in platelet function, immune reactions and how sex hormones affect immune functions, also the effect of androgens on transmembrane protein serine protease 2 (TMPRSS2) receptor in COVID-19 patients was investigated.

Mutation Screening of theHGDGene Identifies a Novel Alkaptonuria Mutation with Significant Founder Effect and High Prevalence

2014 ◽  
Vol 78 (3) ◽  
pp. 155-164 ◽  
Author(s):  
Srinivasan Sakthivel ◽  
Andrea Zatkova ◽  
Martina Nemethova ◽  
Milan Surovy ◽  
Ludevit Kadasi ◽  
...  
Keyword(s):  
Founder Effect ◽  
Mutation Screening ◽  
High Prevalence

scholarly journals High prevalence of a missense mutation of the glucokinase gene in gestational diabetic patients due to a founder-effect in a local population

Diabetologia ◽  
1996 ◽  
Vol 39 (11) ◽  
pp. 1325-1328 ◽  
Author(s):  
P. J. Saker ◽  
A. T. Hattersley ◽  
B. Barrow ◽  
M. S. Hammersley ◽  
J.-A. McLellan ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Founder Effect ◽  
Local Population ◽  
Diabetic Patients ◽  
Glucokinase Gene ◽  
High Prevalence

scholarly journals Prevalence of Everyday Discrimination and Relation with Wellbeing among Aboriginal and Torres Strait Islander Adults in Australia

2021 ◽  
Vol 18 (12) ◽  
pp. 6577
Author(s):  
Katherine Thurber ◽  
Emily Colonna ◽  
Roxanne Jones ◽  
Gilbert Gee ◽  
Naomi Priest ◽  
...  
Keyword(s):  
Large Scale ◽  
Torres Strait Islander ◽  
National Sample ◽  
Indigenous Populations ◽  
Emotional Wellbeing ◽  
Social And Emotional ◽  
High Prevalence ◽  
High Discrimination ◽  
Torres Strait ◽  
Everyday Discrimination

Discrimination is a fundamental determinant of health and health inequities. However, despite the high prevalence of discrimination exposure, there is limited evidence specific to Indigenous populations on the link between discrimination and health. This study employs a validated measure to quantify experiences of everyday discrimination in a national sample of Aboriginal and Torres Strait Islander (Australia’s Indigenous peoples) adults surveyed from 2018 to 2020 (≥16 years, n = 8108). It quantifies Prevalence Ratios (PRs) and 95% Confidence Intervals (CIs) for wellbeing outcomes by level of discrimination exposure, and tests if associations vary by attribution of discrimination to Indigeneity. Of the participants, 41.5% reported no discrimination, 47.5% low, and 11.0% moderate-high. Discrimination was more commonly reported by younger versus older participants, females versus males, and those living in remote versus urban or regional areas. Discrimination was significantly associated in a dose-response manner, with measures of social and emotional wellbeing, culture and identity, health behaviour, and health outcomes. The strength of the association varied across outcomes, from a 10–20% increased prevalence for some outcomes (e.g., disconnection from culture (PR = 1.08; 95% CI: 1.03, 1.14), and high blood pressure (1.20; 1.09, 1.32)), to a five-fold prevalence of alcohol dependence (4.96; 3.64, 6.76), for those with moderate-high versus no discrimination exposure. The association was of consistent strength and direction whether attributed to Indigeneity or not—with three exceptions. Discrimination is associated with a broad range of poor wellbeing outcomes in this large-scale, national, diverse cohort of Aboriginal and Torres Strait Islander adults. These findings support the vast potential to improve Aboriginal and Torres Strait Islander peoples’ wellbeing, and to reduce Indigenous-non-Indigenous inequities, by reducing exposure to discrimination.

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