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).