De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay

• DOI: 10.1371/journal.pgen.1007671
• Publication Date: 2018-11-30T18:32:28Z
• Authors: Susan M. Hiatt; Matthew B. Neu; Ryne C. Ramaker; Andrew A. Hardigan; Jeremy W. Prokop; Miroslava Hancarova; Darina Prchalova; Marketa Havlovicova; Jan Prchal; Viktor Stranecky; Dwight K. C. Yim; Zöe Powis; Boris Keren; Caroline Nava; Cyril Mignot; Marlene Rio; Anya Revah-Politi; Parisa Hemati; Nicholas Stong; Alejandro D. Igle...; Sharon F. Suchy; Rebecca Willaert; Ingrid M. Wentzensen; Patricia G. Wheeler; Lauren Brick; Mariya Kozenko; Anna C. E. Hurst; James W. Wheless; Yves Lacassie; Richard M. Myers; Gregory S. Barsh; Zdenek Sedlacek; Gregory M. Cooper
• Keywords: Small GTPase; Proband; Ras superfamily

Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group Mendelian diseases known as RASopathies. However, among RASopathies, the matrix genotype-phenotype relationships is still incomplete, in part because there are many RAS-related and phenotypic consequences may be variable and/or pleiotropic. Here, we describe cohort ten cases, drawn from six clinical sites over 16,000 sequenced probands, with de novo protein-altering variation RALA, RAS-like small GTPase. All probands present speech motor delays, most have intellectual disability, low weight, short stature, facial dysmorphism. The observed rate RALA variants affected significantly higher (p = 4.93 x 10(-11)) than expected estimated random mutation rate. Further, all described here affect residues within GTP/GDP-binding region RALA; fact, alleles arose at only two codons, Val25 Lys128. highly conserved across both RAL- RAS-family genes, devoid large human population datasets, several homologous positions which disease-associated been other GTPase genes. We directly assayed GTP hydrolysis effector-protein binding variants, found but one tested variant reduced activities compared wild-type. exception, S157A, increased RALA-effector binding, an observation similar seen for oncogenic RAS variants. These results show power data sharing interpretation analysis rare variation, expand spectrum molecular causes developmental disability include provide additional insight into pathogenesis disease caused by mutations GTPases.