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. 2022 Nov 22:13:1047230.
doi: 10.3389/fgene.2022.1047230. eCollection 2022.

A novel heterozygous SIX1 missense mutation resulted in non-syndromic unilateral hearing loss

Ang Li  1 , Siwen Liu  1 , Peng Zhang  1 , Xintong Hu  1 , Guiying Li  2 , Weiyue Gu  2 , Yanfang Jiang  1
Affiliations

A novel heterozygous SIX1 missense mutation resulted in non-syndromic unilateral hearing loss

Ang Li et al. Front Genet. .

Abstract

Familial non-syndromic unilateral hearing loss (NS-UHL) is rare and its genetic etiology has not been clearly elucidated. This study aimed to identify the genetic cause of NS-UHL in a three-generation Chinese family. Detailed medical history consultation and clinical examination were conducted. Further, whole-exome sequencing (WES) was performed to identify the genetic etiology of the proband, and the variant was verified by Sanger sequencing. A novel missense mutation, c.533G>C (p.Arg178Thr), in the SIX homeobox 1 gene (SIX1) was identified in four patients and co-segregated with NS-UHL in a three-generation Chinese family as a dominant trait. Using bioinformatics analyses, we show that this novel mutation is pathogenic and affects the structure of SIX1 protein. These data suggest that mutations in SIX1 gene are associated with NS-UHL. Our study added the NS-UHL phenotype associated with SIX1, and thereby improving the genetic counseling provided to individuals with SIX1 mutations.

Keywords: SIX1 gene; genetic counseling; non-syndromic unilateral hearing loss; novel mutation; whole exome sequencing.

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Conflict of interest statement

GL and WG were employed by the Chigene (Beijing) Translational Medical Research Center Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Pedigree of the family affected by NS-UHL. White symbols indicate normal individuals. The filled black symbol denotes the individual diagnosed with NS-UHL. The arrow indicates the proband of the family.
FIGURE 2
FIGURE 2
Alignment of SIX1 protein sequences from different species. Homo:Homo sapiens (NM_005982.4), Mus: Mus musculus (NM_009189.3), Bos:Bos Taurus (XM_002691019.6), Gallus:Gallus gallus (NM_001044685.2). Red: amino acid containing non-polar and hydrophobic R group, Green: amino acid containing polar and neutral R group, Blue: amino acid containing acidic R group, Purple: amino acid containing basic R group. “*”: a completely consistent residue, “.”: residues with weak and similar properties, “:”: residues with very similar properties.
FIGURE 3
FIGURE 3
Prediction of the tertiary structure of SIX1 protein. The novel variant of the SIX1 gene is c.533 G>C, p.R178T (p.Arg178Thr), (A) is the 3D overall picture of wild-type (WT) SIX1 protein: the 178th amino acid is ARG. (B) is the 3D partial enlarged view of WT SIX1 protein. The 178ARG respectively form a hydrogen bond with the 123ASP, 127THR, 175 ARG, and 182 ALA, and 178ARG form two hydrogen bonds with 174ASN, together to maintain the stability of the protein structure. (C) is the 3D overall picture of mutant (MUT) SIX1 protein: the 178th amino acid is mutated to THR. (D) is the 3D partial enlarged view of mutant SIX1 protein. No hydrogen bond interaction existed between the 178THR and 123ASP, 127THR.
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