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Volume 51 Issue 12
Dec.  2024
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Article Navigation >  Journal of Genetics and Genomics  > 2024  >  51(12): 1389-1403

RFC2 may contribute to the pathogenicity of Williams syndrome revealed in a zebrafish model

doi: 10.1016/j.jgg.2024.09.016
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    a. Department of Biology, Chungnam National University, Daejeon 34134, Republic of Korea;

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    b. Department of Pediatrics, The University of Texas at Austin Dell Medical School, Austin, TX 78723, USA;

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    c. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA;

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    d. Baylor Genetics Laboratories, Houston, TX 77021, USA;

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    e. Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea;

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    f. Univ. Lille, CHU Lille, Clinique de génétique Guy Fontaine, F-59000 Lille, France;

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    g. Department of Pediatrics, Chungnam National University Sejong Hospital, Sejong 30099, Republic of Korea;

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    h. Department of Pediatrics, Pusan National University Children's Hospital, Yangsan 50612, Republic of Korea;

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    i. Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea;

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    j. Clinical Research Institute, Kyung Hee University Hospital at Gangdong, School of Medicine, Kyung Hee University, Seoul 05278, Republic of Korea

Funds:

This work was supported by the National Research Foundation of Korea grant funded by the Korean government (MIST) (2020R1A5A8017671, 2022R1A2C100677813, and RS-2024-00349650). C.K.C. was supported by a 2023 research grant from Pusan National University Yangsan Hospital. Y.M.K. was supported by the Korea National Institute of Health research project (No. 2022ER050800).

  • Received Date: 2024-05-30
  • Accepted Date: 2024-09-27
  • Rev Recd Date: 2024-09-27
    • Available Online: 2025-06-05
  • Publish Date: 2024-10-04
    Abstract

  • Williams syndrome (WS) is a rare multisystemic disorder caused by recurrent microdeletions on 7q11.23, characterized by intellectual disability, distinctive craniofacial and dental features, and cardiovascular problems. Previous studies have explored the roles of individual genes within these microdeletions in contributing to WS phenotypes. Here, we report five patients with WS with 1.4 Mb-1.5 Mb microdeletions that include RFC2, as well as one patient with a 167-kb microdeletion involving RFC2 and six patients with intragenic variants within RFC2. To investigate the potential involvement of RFC2 in WS pathogenicity, we generate a rfc2 knockout (KO) zebrafish using CRISPR-Cas9 technology. Additionally, we generate a KO zebrafish of its paralog gene, rfc5, to better understand the functions of these RFC genes in development and disease. Both rfc2 and rfc5 KO zebrafish exhibit similar phenotypes reminiscent of WS, including small head and brain, jaw and dental defects, and vascular problems. RNA-seq analysis reveals that genes associated with neural cell survival and differentiation are specifically affected in rfc2 KO zebrafish. In addition, heterozygous rfc2 KO adult zebrafish demonstrate an anxiety-like behavior with increased social cohesion. These results suggest that RFC2 may contribute to the pathogenicity of WS, as evidenced by the zebrafish model.

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