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

Jun Shinagawa,Shin-Ichi Usami,Hideaki Moteki,Yoshihiro Noguchi,Shin-Ya Nishio

doi:10.3390/genes11030250

Abstract

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.

Highlights

Congenital hearing loss affects approximately one in 500–1000 infants in developed countries, and genetic causes account for at least 50% of all childhood onset non-syndromic sensorineural hearing loss [1]
The c.35delG mutation is commonly observed in European, American, North African, and Middle Eastern populations, but this mutation is rarely observed in the Japanese population, whereas the c.235delC mutation is commonly observed in the Japanese population, but this mutation is relatively rare in European and American populations [4]
We enrolled 7,408 sensorineural hearing loss patients, and extracted about 20 patients with each each homozygous GJB2 mutation frequently identified in the Japanese population

Summary

Introduction

Congenital hearing loss affects approximately one in 500–1000 infants in developed countries, and genetic causes account for at least 50% of all childhood onset non-syndromic sensorineural hearing loss [1]. It is estimated that there are more than 100 causative genes related to non-syndromic hereditary hearing loss [2], with the most frequent deafness-associated gene worldwide being the GJB2 gene. Hearing loss caused by GJB2 gene mutations is divided into autosomal recessive inheritance (DFNB1A) and autosomal dominant inheritance (DFNA3A), but most cases of GJB2-associated hearing loss are autosomal recessive inheritance. The allele frequency of GJB2 gene mutations in the normal. Japanese population is approximately 2% [3]. Regarding GJB2 mutations, recurrent mutations are known to differ among ethnic groups. The c.35delG mutation is commonly observed in European, American, North African, and Middle Eastern populations, but this mutation is rarely observed in the Japanese population, whereas the c.235delC mutation is commonly observed in the Japanese population, but this mutation is relatively rare in European and American populations [4]

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Discussion

Conclusion