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Zebrafish modeling mimics developmental phenotype of patients with RAPGEF1 mutation
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  • Na Li,
  • Pei Zhou,
  • Miaomiao Yang,
  • Xiang Fang,
  • Nadine Krämer,
  • Tauqeer Ahmed Mughal,
  • Ansar Abbassi,
  • Angela Kaindl,
  • Hao Hu
Na Li
Guangzhou Women and Children's Medical Center
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Pei Zhou
Guangzhou Women and Children's Medical Center
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Miaomiao Yang
Guangzhou Women and Children's Medical Center
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Xiang Fang
Guangzhou Women and Children's Medical Center
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Nadine Krämer
Charité Universitätsmedizin Berlin
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Tauqeer Ahmed Mughal
Mirpur University of Science and Technology
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Ansar Abbassi
Department of Zoology
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Angela Kaindl
Charité Universitätsmedizin Berlin
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Hao Hu
Guangzhou Women and Children's Medical Center
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Abstract

RAPGEF1 is a guanine nucleotide exchange factor responsible for transmitting extracellular signals to the Ras family of GTPase located at the inside of membrane. Here, we report for the first time a homozygous mutation of RAPGEF1 in a consanguineous family with two siblings affected by neuropsychiatric disorder. To confirm the correlation of the mutation and the phenotype, we utilized in silico analysis and established a zebrafish model. Survival rate was reduced in the rapgef1a-knockdown model, and the zebrafish showed global morphological abnormalities, particularly of brain and blood vessels. Co-application of human RAPGEF1 wildtype mRNA effectively rescued the abnormal phenotype, while that of RAPGEF1 mRNA carrying the human mutation did not. This work is the first report of a human Mendelian disease associated with RAPGEF1 and the first report of a zebrafish model built for this gene. The phenotype of zebrafish model provides further evidence that defective RAPGEF1 may lead to global developmental delay in human patients.