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

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. IglesiasSharon F. Suchy, Rebecca Willaert, Ingrid M. Wentzensen, Patricia G. Wheeler, Lauren Brick, Mariya Kozenko, Anna C.E. Hurst, James Wheless, Yves Lacassie, Richard M. Myers, Gregory S. Barsh, Zdenek Sedlacek, Gregory M. Cooper

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Article numbere1007671
JournalPLoS genetics
Volume14
Issue number11
DOIs
StatePublished - Nov 1 2018

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Monomeric GTP-Binding Proteins
disability
guanosinetriphosphatase
Guanosine Triphosphate
Gross Domestic Product
Intellectual Disability
mutation
Mutation
protein
Hydrolysis
hydrolysis
Language Development Disorders
Developmental Disabilities
Proteins
proteins
Information Dissemination
GTP Phosphohydrolases
protein binding
Mutation Rate
human diseases

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Hiatt, S. M., Neu, M. B., Ramaker, R. C., Hardigan, A. A., Prokop, J. W., Hancarova, M., ... Cooper, G. M. (2018). De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay. PLoS genetics, 14(11), [e1007671]. https://doi.org/10.1371/journal.pgen.1007671

De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay. / 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; Lacassie, Yves; Myers, Richard M.; Barsh, Gregory S.; Sedlacek, Zdenek; Cooper, Gregory M.

In: PLoS genetics, Vol. 14, No. 11, e1007671, 01.11.2018.

Research output: Contribution to journalArticle

Hiatt, SM, Neu, MB, Ramaker, RC, Hardigan, AA, Prokop, JW, Hancarova, M, Prchalova, D, Havlovicova, M, Prchal, J, Stranecky, V, Yim, DKC, Powis, Z, Keren, B, Nava, C, Mignot, C, Rio, M, Revah-Politi, A, Hemati, P, Stong, N, Iglesias, AD, Suchy, SF, Willaert, R, Wentzensen, IM, Wheeler, PG, Brick, L, Kozenko, M, Hurst, ACE, Wheless, J, Lacassie, Y, Myers, RM, Barsh, GS, Sedlacek, Z & Cooper, GM 2018, 'De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay', PLoS genetics, vol. 14, no. 11, e1007671. https://doi.org/10.1371/journal.pgen.1007671
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 ; Lacassie, Yves ; Myers, Richard M. ; Barsh, Gregory S. ; Sedlacek, Zdenek ; Cooper, Gregory M. / De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay. In: PLoS genetics. 2018 ; Vol. 14, No. 11.
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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.",
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T1 - De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay

AU - Hiatt, Susan M.

AU - Neu, Matthew B.

AU - Ramaker, Ryne C.

AU - Hardigan, Andrew A.

AU - Prokop, Jeremy W.

AU - Hancarova, Miroslava

AU - Prchalova, Darina

AU - Havlovicova, Marketa

AU - Prchal, Jan

AU - Stranecky, Viktor

AU - Yim, Dwight K.C.

AU - Powis, Zöe

AU - Keren, Boris

AU - Nava, Caroline

AU - Mignot, Cyril

AU - Rio, Marlene

AU - Revah-Politi, Anya

AU - Hemati, Parisa

AU - Stong, Nicholas

AU - Iglesias, Alejandro D.

AU - Suchy, Sharon F.

AU - Willaert, Rebecca

AU - Wentzensen, Ingrid M.

AU - Wheeler, Patricia G.

AU - Brick, Lauren

AU - Kozenko, Mariya

AU - Hurst, Anna C.E.

AU - Wheless, James

AU - Lacassie, Yves

AU - Myers, Richard M.

AU - Barsh, Gregory S.

AU - Sedlacek, Zdenek

AU - Cooper, Gregory M.

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