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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Primary Immunodeficiencies
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1460990
This article is part of the Research Topic Advancing Research, Clinical Recognition, and Targeted Therapies for WHIM Syndrome View all 4 articles

Heterogeneous phenotype of a Chinese Familial WHIM Syndrome with CXCR4 V340fs Gain-of-function Mutation

Provisionally accepted
Yu Huang Yu Huang 1,2,3Lu Li Lu Li 2,3,4Ran Chen Ran Chen 2,3Lang Yu Lang Yu 2,3Shun k. Zhao Shun k. Zhao 5Yan j. Jia Yan j. Jia 2,3,4Ying Dou Ying Dou 1,2,3Zhi y. Zhang Zhi y. Zhang 2,3,6Yun f. An Yun f. An 2,3,6Xue m. Tang Xue m. Tang 2,3,6Xiao d. Zhao Xiao d. Zhao 2,3,6*Li n. Zhou Li n. Zhou 2,3*
  • 1 Division of Hematology and Oncology, Children’s Hospital of Chongqing Medical University, Chongqing, China
  • 2 Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
  • 3 Chongqing Key Laboratory of Child Infection and Immunity, Children 's Hospital, Chongqing Medical University, Chongqing, China
  • 4 Children‘s Hospital of Chongqing Medical University, Chongqing, China
  • 5 Department of Biology, School of Arts and Sciences, Tufts University, Medford, Massachusetts, United States
  • 6 Department of Rheumatology & Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China

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

    Background: WHIM syndrome is a rare, autosomal dominant inborn error of immunity characterized by warts, hypogammaglobulinemia, infection, and myelokathexis. It is caused mainly by heterozygous mutations at the C-terminus of the C-X-C chemokine receptor type 4 (CXCR4) gene. Methods: We described the detailed clinical, genetic, immunological and treatment characteristic of four WHIM patients from a single Chinese family. Results: Here, we report four patients from a family carring a variant of CXCR4 (c.1016_1017dupCT), which introduces a frameshift at codon V340, resulting in an extension of 14 amino acids (p.V340L fs*27). We provide and in-depth analysis of their clinical, genetic, immunological and treatment characteristic, noting that these patients exhibited an atypical clinical phenotype when compared to reported CXCR4R334X patients. Additionally, the frameshift variant CXCR4V340fs led to impaired receptor downregulation in patients’ PBMCs, and in HEK293T cells transfected with the variant plasmids. Conclusions: Our study provided detailed clinical features of four CXCR4V340fs WHIM patients from one Chinese family who presented atypical phenotype and enrich the spectrum of WHIM syndrome.

    Keywords: CXCR4 variant, gain-of-function, Inborn error of immunity, WHIM syndrome, Heterogeneous phenotype

    Received: 07 Jul 2024; Accepted: 23 Oct 2024.

    Copyright: © 2024 Huang, Li, Chen, Yu, Zhao, Jia, Dou, Zhang, An, Tang, Zhao and Zhou. 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:
    Xiao d. Zhao, Chongqing Key Laboratory of Child Infection and Immunity, Children 's Hospital, Chongqing Medical University, Chongqing, China
    Li n. Zhou, Chongqing Key Laboratory of Child Infection and Immunity, Children 's Hospital, Chongqing Medical University, Chongqing, China

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