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ORIGINAL RESEARCH article

Front. Genet.
Sec. Genetics of Common and Rare Diseases
Volume 15 - 2024 | doi: 10.3389/fgene.2024.1433060

Novel WFS1 variants are associated with different diabetes phenotypes

Provisionally accepted
Lei Wu Lei Wu Juan Zhang Juan Zhang Danjie Li Danjie Li Zhongyun Zhang Zhongyun Zhang Qicheng Ni Qicheng Ni Rulai Han Rulai Han Lei Ye Lei Ye Yifei Zhang Yifei Zhang Weiqing Wang Weiqing Wang Guang Ning Guang Ning Weiqiong Gu Weiqiong Gu *
  • Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

The final, formatted version of the article will be published soon.

    Background: The WFS1 gene encodes the protein wolframin, which is crucial for maintaining endoplasmic reticulum homeostasis. Variants in this gene are predominantly associated with Wolfram syndrome and have been implicated in other disorders such as diabetes mellitus and psychiatric diseases, which increases the rate of clinical misdiagnosis. Methods: Patients were diagnosed with early-onset unclassified diabetes according to their clinical and laboratory data. We performed whole-exome sequencing (WES) in 165 patients, interpreting variants according to the American College of Medical Genetics/Association for Molecular Pathology (ACMG/AMP) 2015 guidelines. Variant verification was done by Sanger sequencing. In vitro experiments were conducted to evaluate the effects of WFS1 compound heterozygous variants. Results: We identified WFS1 compound heterozygous variants (p.A214fs*74/p.F329I and p.I427S/p.I304T) in two patients with Wolfram Syndrome-Like disorders (WSLD). Both WFS1 compound heterozygous variants were associated with increased ER stress, reduced cell viability, and decreased SERCA2b mRNA levels. Additionally, pathogenic or likely pathogenic WFS1 heterozygous variants were identified in the other three patients. Conclusion: Our results underscore the importance of early genetic testing for diagnosing young-onset diabetes and highlight the clinical relevance of WFS1 variants in increasing ER stress and reducing cell viability. Incorporating these genetic insights into clinical practice can reduce misdiagnoses and improve treatment strategies for related disorders.

    Keywords: WFS1 gene, Wolfram Syndrome-Like disorders (WSLD), ACMG classification, Functional Analysis, whole-exome sequencing (WES)

    Received: 15 May 2024; Accepted: 31 Jul 2024.

    Copyright: © 2024 Wu, Zhang, Li, Zhang, Ni, Han, Ye, Zhang, Wang, Ning and Gu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Weiqiong Gu, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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