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. 2023 Apr 11;16(1):79.
doi: 10.1186/s12920-023-01506-x.

WFS1 autosomal dominant variants linked with hearing loss: update on structural analysis and cochlear implant outcome

Hui Dong Lim  1 , So Min Lee  1 , Ye Jin Yun  1 , Dae Hee Lee  2 , Jun Ho Lee  1 , Seung-Ha Oh  1 , Sang-Yeon Lee  3   4
Affiliations

WFS1 autosomal dominant variants linked with hearing loss: update on structural analysis and cochlear implant outcome

Hui Dong Lim et al. BMC Med Genomics. .

Abstract

Background: Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome, WFS1 heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified two WFS1 heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of the WFS1 variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes in WFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review.

Methods: We performed molecular genetic test and evaluated clinical phenotypes of three WFS1-associated DFNA6/14/38 families. A putative WFS1-NCS1 interaction model was generated, and the impacts of WFS1 variants on stability were predicted by comparing intramolecular interactions. A total of 62 WFS1 variants associated with DFNA6/14/38 were included in a systematic review.

Results: One variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7-9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val in WFS1 is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI.

Conclusions: We expanded the genotypic spectrum of WFS1 heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits for WFS1 heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.

Keywords: Cochlear implantation; DFNA6/14/38; Structure analysis; WFS1; Wolfram-like syndrome.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
A schematic overview of the WFS1 protein, pedigrees of the three families, the audio-logical phenotypes of affected probands, and Sanger sequencing traces of the WFS1 variants. (A) Pedigrees of three families with WFS1 heterozygous variants and associated audiograms. (B) Physical map of WFS1, which contains nine transmembrane domains and an ER-luminal domain. The domains are represented as in the Universal Protein Resource (UniProt) database. The novel frameshift variant in SH486 (c.1544_1545insA:p.Phe515LeufsTer28) and the missense variant in SH550 andSH592 (c.2051 C > T:p.Ala684Val) reside in TM domain 6 and the ER-luminal domain, respectively. Conservation of the corresponding residues between species is depicted. (C) Sanger chromatogram of the respective WFS1 heterozygous variants. All probands were confirmed as de novo occurrences
Fig. 2
Fig. 2
3D modeling and structural analysis of WFS1 p.Ala684Val. (A) WFS1 3D model generated from Alphafold (green). Ala684/Arg685 are located at the alpha-helix (Cyan, Met683-His692) of the ER-luminal domain. (B) Putative WFS1(Alphafold model) – NCS1(4GUK) interaction model generated by PyDock software. Arg685 extrudes from alpha helix (helix A) and directly interacts with NCS1 Phe50 via cation-π interaction (black dashes). (C) Loss of WFS1-NCS1 interaction in p.Arg685Pro. The p.Arg685Pro mutant loses its own cation- π interaction, which is required for WFS1-NCS1 interaction. Moreover, proline substitution breaks helix A [1], contributing to the loss of NCS1 interaction [2]. (D) Non-polar, hydrophobic substitution of A684 induces helix destabilization and distorts helix A [1]. The side chain of R685 in twisted helix A may tilt from its original position [2], disrupting NCS1 binding [3] (grey dashes)
Fig. 3
Fig. 3
3D modeling and structural analysis of WFS1 p.Phe515LeufsTer28. WFS1 3D model generated from Colabfold. (A) WFS1 Wild type (B) WFS1 p.Phe515LeufsTer28. Cytoplasmic domain (cyan), TM domain (green), ER-luminal domain (blue). More than one-third of the length of the protein is truncated, including TM domain 7–9 and the ER-luminal domain. Conformational changes of WFS1 mutant (p.Phe515LeufsTer28) were observed
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References

    1. Davis A, Davis K. Descriptive epidemiology of childhood hearing impairment.Comprehensive handbook of pediatric audiology. 2011:85–111.
    1. Morton CC, Nance WE. Newborn hearing screening — a Silent Revolution. N Engl J Med. 2006;354(20):2151–64. doi: 10.1056/NEJMra050700. - DOI - PubMed
    1. Van Camp G. Hereditary hearing loss homepage. URL: https://hereditaryhearingloss.org. 2006.
    1. Jo HD, Han JH, Lee SM, Choi DH, Lee S-Y, Choi BY. Genetic load of alternations of transcription factor genes in non-syndromic deafness and the Associated Clinical Phenotypes: experience from two Tertiary Referral Centers. Biomedicines. 2022;10(9):2125. doi: 10.3390/biomedicines10092125. - DOI - PMC - PubMed
    1. Lee S-Y, Choi HB, Park M, Choi IS, An J, Kim A, et al. Novel KCNQ4 variants in different functional domains confer genotype-and mechanism-based therapeutics in patients with nonsyndromic hearing loss. Exp Mol Med. 2021;53(7):1192–204. doi: 10.1038/s12276-021-00653-4. - DOI - PMC - PubMed

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