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.