Unveiling a novel GJB2 dominant K22T mutation in a Chinese family with hearing loss

Abstract

Hearing loss constitutes one of the most prevalent conditions within the field of otolaryngology. Recent investigations have revealed that mutations in deafness-associated genes, including point mutations and variations in DNA sequences, can cause hearing impairments. With the ethology of deafness remaining unclear for a substantial portion of the affected population, further screenings for pathogenic mutations are imperative to unveil the underlying mechanisms. On this study, by using next-generation sequencing, we examine 129 commonly implicated deafness-related genes in a Chinese family with hearing loss, revealing a novel heterozygous dominant mutation in the GJB2 gene (GJB2: c.65T>G: p. Lys22Thr). This mutation consistently occurs in affected family members but is not detected in unaffected individuals, strongly suggesting its causative role in hearing loss. Structural analysis indicates potential disruption to the Cx26 gap junction channel’s hydrogen bond and electrostatic interactions, aligning with predictions from the PolyPhen and SIFT algorithms. In conclusion, our study provides conclusive evidence that the identified heterozygous GJB2 mutation (GJB2: c.65T>G: p. Lys22Thr), specifically the K22T alteration, is the primary determinant of the family’s deafness. This contribution enhances our understanding of the interplay between common deafness-associated genes and hearing loss, offering valuable insights for diagnostic guidance and the formulation of therapeutic strategies for this condition.

1. Introduction

Hearing loss, a prevalent sensory impairment, affects a substantial portion of the global populace, with an estimated 5% of individuals worldwide experiencing this condition [1]. Among these, congenital or prelingual deafness impacts approximately 1 in 1000 children [2‒4]. The ramifications of hearing loss are profound, encompassing challenges in language acquisition, hindered educational attainment, and the potential for psychological distress, social isolation, and reduced quality of life (QOL) [1,5,6]. Consequently, elucidating the intricate mechanisms governing hearing loss holds great promise for advancing therapeutic strategies.

The etiology of hearing loss arises from a complex interplay of factors, including genetic predisposition, aging, pharmaceutical influences, and viral infections [4,7]. Notably, genetic factors account for approximately 60% of congenital sensorineural hearing loss cases [8,9]. In recent years, a comprehensive repertoire of genes associated with deafness has emerged, with point mutations within these genes identified as causative agents in various hearing loss cases [10]. Noteworthy examples include mutations in the GJB2 gene encoding connexin26 (Cx26), which is responsible for more than half of autosomal recessive non-syndromic hearing loss cases [8,11‒13]. Additionally, mutations in GJB4 (Cx30.3), including frameshift mutations and amino acid variants such as R103C, R124Q, R160C, C169W, and E204A, have been linked to non-syndromic hearing loss [14,15]. Moreover, genes such as USH2A, USH2C, and USH2D have been implicated in Usher syndrome, a hereditary disorder characterized by combined auditory and visual impairment [16,17]. Further expanding the genetic spectrum, mutations in the KCNQ1 gene have been associated with Jervell and Lange-Nielsen (JNL) syndrome, which features congenital deafness alongside prolonged QT intervals in electrocardiograms [17,18]. Despite these advancements, a significant proportion of affected individuals still lack a clear etiological understanding of their deafness, underscoring the need to elucidate the intricate relationship between hearing loss and deafness-associated genes. Thus, a systematic identification of pathogenic mutations remains pivotal, which will shed light on the mechanistic underpinnings of deafness and offer prospects for targeted therapeutic interventions [19,20].

Distinct from the predominant autosomal recessive pattern associated with most GJB2 point mutations, instances of autosomal dominant non-syndromic hearing loss have been well documented [21]. Notably, individuals who experience both hearing impairment and skin disorders often exhibit a dominant pattern of syndromic inheritance. In contrast, our investigation revealed a novel heterozygous mutation linked specifically to non-syndromic phenotypes, notably without any occurrence of skin-related conditions among the family members. This distinction is of paramount importance, considering that non-syndromic deafness primarily arises from loss-of-function mutations, while the literature u