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De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder.

ABSTRACT: DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

SUBMITTER: Lessel D

PROVIDER: S-EPMC5673606 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder.

Lessel Davor D Schob Claudia C Küry Sébastien S Reijnders Margot R F MRF Harel Tamar T Eldomery Mohammad K MK Coban-Akdemir Zeynep Z Denecke Jonas J Edvardson Shimon S Colin Estelle E Stegmann Alexander P A APA Gerkes Erica H EH Tessarech Marine M Bonneau Dominique D Barth Magalie M Besnard Thomas T Cogné Benjamin B Revah-Politi Anya A Strom Tim M TM Rosenfeld Jill A JA Yang Yaping Y Posey Jennifer E JE Immken LaDonna L Oundjian Nelly N Helbig Katherine L KL Meeks Naomi N Zegar Kelsey K Morton Jenny J Schieving Jolanda H JH Claasen Ana A Huentelman Matthew M Narayanan Vinodh V Ramsey Keri K Brunner Han G HG Elpeleg Orly O Mercier Sandra S Bézieau Stéphane S Kubisch Christian C Kleefstra Tjitske T Kindler Stefan S Lupski James R JR Kreienkamp Hans-Jürgen HJ

American journal of human genetics 20171101 5

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly co ...[more]

PMID: 29100085

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Dataset Information

De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder.

Publications

De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder.

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