PLoS genetics · 2018
De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Hiatt Susan M, Neu Matthew B, Ramaker Ryne C, Hardigan Andrew A, Prokop Jeremy W, Hancarova Miroslava, Prchalova Darina, Havlovicova Marketa, Prchal Jan, Stranecky Viktor, Yim Dwight K C, Powis Zöe, Keren Boris, Nava Caroline, Mignot Cyril, Rio Marlene, Revah-Politi Anya, Hemati Parisa, Stong Nicholas, Iglesias Alejandro D, Suchy Sharon F, Willaert Rebecca, Wentzensen Ingrid M, Wheeler Patricia G, Brick Lauren, Kozenko Mariya, Hurst Anna C E, Wheless James W, Lacassie Yves, Myers Richard M, Barsh Gregory S, Sedlacek Zdenek, Cooper Gregory M
Аннотация
Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p = 4.93 x 10(-11)) than expected from the estimated random mutation rate. Further, all de novo variants described here affect residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. The affected residues are highly conserved across both RAL- and RAS-family genes, are devoid of variation in large human population datasets, and several are homologous to positions at which disease-associated variants have been observed in other GTPase genes. We directly assayed GTP hydrolysis and RALA effector-protein binding of the observed variants, and found that all but one tested variant significantly reduced both activities compared to wild-type. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases.