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PLoS Genet. 2018 Nov 30;14(11):e1007671. doi: 10.1371/journal.pgen.1007671. eCollection 2018 Nov.

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

Author information

1
HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States of America.
2
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States of America.
3
Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI, United States of America.
4
Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
5
Laboratory of NMR Spectroscopy, University of Chemistry and Technology, Prague, Czech Republic.
6
Department of Pediatrics and Adolescent Medicine, Diagnostic and Research Unit for Rare Diseases, Charles University 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.
7
Kaiser Permanente-Hawaii, Honolulu, HI, United States of America.
8
Department of Emerging Genetic Medicine, Ambry Genetics, Aliso Viejo, CA, United States of America.
9
Department of Genetics, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
10
Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France.
11
Groupe de Recherche Clinique UPMC "Déficience Intellectuelle et Autisme", Paris, France.
12
Assistance Publique-Hôpitaux de Paris, service de Génétique, Hôpital Necker-Enfants-Malades, Paris, France.
13
Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, United States of America.
14
Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center, New York, NY, United States of America.
15
GeneDx, Gaithersburg, MD, United States of America.
16
Arnold Palmer Hospital, Division of Genetics, Orlando, FL, United States of America.
17
Department of Genetics, McMaster Children's Hospital, Hamilton, Ontario, Canada.
18
Division of Pediatric Neurology, University of Tennessee Health Science Center, Neuroscience Institute & Le Bonheur Comprehensive Epilepsy Program, Memphis, TN, United States of America.
19
Le Bonheur Children's Hospital, Memphis, TN, United States of America.
20
Division of Clinical Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, United States of America.
21
Department of Genetics, Children's Hospital, New Orleans, LA, United States of America.

Abstract

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.

PMID:
30500825
DOI:
10.1371/journal.pgen.1007671
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Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: GMC is currently serving as an Academic Editor for PLOS Genetics. GSB is currently serving as an Editor-In-Chief for PLOS Genetics. ZP is an employee of Ambry Genetics, which provides exome sequencing as a commercially available test. IMW, RW, SFS are employees of GeneDx, Inc., a wholly owned subsidiary of OPKO Health, Inc. that also offers commercial exome sequencing. The remaining authors declare no conflicts of interest.

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