RFC2 may contribute to the pathogenicity of Williams syndrome revealed in a zebrafish model
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.
Authors
- Laurie Robak (ORCID: https://orcid.org/0000-0001-8279-2504)
- Florence Petit (ORCID: https://orcid.org/0000-0002-1368-1023)
- Yoo‐Mi Kim (ORCID: https://orcid.org/0000-0002-8440-5069)
- Tae‐Ik Choi (ORCID: https://orcid.org/0000-0003-2667-3804)
- Yoonsung Lee (ORCID: https://orcid.org/0000-0001-9934-2390)
- Chong Kun Cheon (ORCID: https://orcid.org/0000-0002-8609-5826)
- T. Kim (ORCID: https://orcid.org/0009-0005-9147-0685)
- Jaya K. George‐Abraham (ORCID: https://orcid.org/0000-0001-8686-8107)
- Jill Anne Rosenfeld (ORCID: https://orcid.org/0000-0001-5664-7987)
- Dilan Wellalage Don (ORCID: https://orcid.org/0000-0003-3372-0349)
- Jiwon Park (ORCID: https://orcid.org/0009-0001-7324-2567)
- Pengfei Liu (ORCID: https://orcid.org/0000-0002-4177-709X)
- Cheol‐Hee Kim (ORCID: https://orcid.org/0000-0002-3019-0699)
- Yu‐Ri Lee (ORCID: https://orcid.org/0000-0003-1365-8680)
- Tae Hyeong Kim (ORCID: https://orcid.org/0000-0002-0243-7148)
- Cristina C Trandafir
Institutions
- Baylor College of Medicine (US)
- Chungnam National University (KR)
- Université de Lille (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Chungnam National University Hospital (KR)
- Pusan National University Yangsan Hospital (KR)
- Kyung Hee University Hospital at Gangdong (KR)
- Baylor Genetics (US)
- The University of Texas at Austin (US)
Publication Details
- Journal
- Journal of genetics and genomics/Journal of Genetics and Genomics
- Published
- 2024-10-04
- DOI
- https://doi.org/10.1016/j.jgg.2024.09.016
- Citations
- 1
- Primary Topic
- Williams Syndrome Research
- Type
- article
- Field-Weighted Citation Impact
- 0.41
Funders
- Wellcome Trust
- European Bioinformatics Institute
- Korea Disease Control and Prevention Agency
- National Research Foundation
- Pusan National University
- National Research Foundation of Korea
- Pusan National University Hospital
- Ministry of Science and ICT, South Korea
- Korea National Institute of Health