Detection of a RAPGEF2de novo
variant (p.E1357K) in a sALS trio. (A) Family pedigree. Square indicates male; circle, female; and solid, affected. (B) Confirmation of the p.E1357K variant in RAPGEF2
by Sanger sequencing. (C) Domain architecture of the human RAPGEF2 protein along with the position of the identified substitution. Conserved domains are identified by SMART (Simple Modular Architecture Research Tool, http://smart.embl-heidelberg.de
) and PONDR (Predictor of Natural Disordered Regions, http://www.pondr.com
). The asterisk indicates the position of the substitution p.E1357K within the second LCD domain of RAPGEF2. Note that the amino acid E1357 is highly conserved among species. cNMP, cyclic nucleotide monophosphate-binding; Ras-GEFN, the N-terminal domain of guanine nucleotide exchange factor for Ras-like GTPases; PDZ, PSD-95/Dlg/ZO-1 binding domain; RA, Ras/Rap association; RasGEF, guanine nucleotide exchange factor for Ras-like GTPases; LCD, low-complexity domain.