Discussion:
GTPase-coupled signaling pathways play crucial roles on a multitude of biological functioning scenarios. Among a constellation of genes involved in this signaling pathway, RAPGEF1 is a guanine nucleotide exchange factor responsible for transmitting extracellular signals to the Ras family of GTPase located at the inside of membrane. Mouse modeling unveiled part of the essential roles of RAPGEF1 in embryonic development, especially that of brain and vessels. However, the involvement of RAPGEF1 in human Mendelian disease has not yet been identified, although it is intuitive to suppose that the defect ofRAPGEF1 should lead to human disease. Here we report for the first time a case in which two patients with intellectual disability were found to harbor a homozygous mutation of RAPGEF1 . The correlation of this gene and its mutation with the phenotype was substantiated by genetic analysis and a series of in silicoprediction. Furthermore, we established a zebrafish model to mimic the symptoms of patients. To the best of our knowledge, this is the first reported zebrafish model for RAPGEF1 . We confirmed the defectiverapgef1a , a homologous gene of zebrafish, caused decreased survival rate and abnormal gross morphology including brain pattern and body axis. This model showed significant reduction in movement performance, and an irregular outgrowth of motor neuron axon. Simultaneously, the knockdown of rapgef1a led to observable problems in vascular structure and somitogenesis. As a proof-of-concept that the human variant is pathogenic, human wildtype RAPGEF1 mRNA could largely rescue the abnormal phenotype while the mRNA with the human mutation could not. This finding confirmed the deleterious effect of the human mutation of RAPGEF1 . To delve into the underlying molecular mechanism of RAPGEF1 , the zebrafish model that we constructed would be a very good tool, especially in the fields of nervous system and blood vessel development (Covassin et al., 2006; Siekmann & Lawson, 2007).