Using whole exome sequencing (WES) of a patient-parent trio, a de novo variant in the RAPGEF2 gene was identified in a patient with early-onset sporadic amyotrophic lateral sclerosis (ALS). The variant acts as a dominant; RAPGEF2 is an autosomal gene. RAPGEF2 protein functions as a guanine nucleotide exchange factor and serves as a link between cell surface receptors and RAS activation. RAPGEF2 has previously been implicated in a form of epilepsy (MIM:618075). There is a single orthologous gene in Drosophila, PDZ-GEF, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and amorphic alleles resulting from imprecise excision of TE insertions have been generated. There is a second paralogous gene in human, RAPGEF6.
Several UAS constructs of the human Hsap\RAPGEF2 gene, including wild-type and mutant for the implicated variant, have been introduced into flies. Variant(s) implicated in human disease tested (as transgenic human gene, RAPGEF2): the E1357K variant form has been introduced into flies. The detected variant is in an amino acid conserved from human and other vertebrates to Drosophila, within a low-complexity domain. In the fly, overexpression of the Hsap\RAPGEF2 E1357K variant in motor neurons impairs microtubule stability and mitochondrial distribution along axons and at NMJ presynaptic terminals; overexpression of the wild-type human gene has no effect on axonal microtubule stability.
Animals carrying loss-of-function alleles of Dmel\PDZ-GEF are typically sterile; survival to adulthood is reduced. RNAi-mediated knockdown of PDZ-GEF in motor neurons results in increased synaptic growth at the NMJ; this and other observed phenotypes are opposite those observed for the Hsap\RAPGEF2 E1357K variant. Genetic interactions have been described for Dmel\PDZ-GEF; see the PDZ-GEF gene report.
[updated Mar. 2019 by FlyBase; FBrf0222196]
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996, pubmed:8875253). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. [from MIM:105400, 2015.02.11]
The patient developed progressive weakness first in the lower limbs and then in the upper limbs from 27 years of age. Neurologic examination showed clinical signs of upper motor neuron involvement, mild hand wasting, and fasciculation in the lower limbs (FBrf0241135).
RAPGEF2 protein functions as a guanine nucleotide exchange factor (GEF), which activates RAP and RAS small GTPases by exchanging bound GDP for free GTP in a cAMP-dependent manner. Guanine nucleotide exchange factors such as RAPGEF2 serve as RAS activators by promoting acquisition of GTP to maintain the active GTP-bound state, and are the key link between cell surface receptors and RAS activation. [Gene Cards, RAPGEF2; 2019.03.19]
Many to one: 2 human to 1 Drosophila. The two human genes are RAPGEF2 and RAPGEF6.
High-scoring ortholog of human RAPGEF2 and RAPGEF6 (1 Drosophila to 2 human). Dmel\PDZ-GEF shares 34-35% identity and 48-49% similarity with the human genes.
