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Am J Hum Genet. 2017 Nov 2;101(5):716-724. doi: 10.1016/j.ajhg.2017.09.014.

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

Author information

1
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Undiagnosed Disease Program at the University Medical Center Hamburg-Eppendorf (UDP-UKE), Martinistraße 52, 20246 Hamburg, Germany. Electronic address: d.lessel@uke.de.
2
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
3
CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes Cedex, France.
4
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
5
Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 9112001.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
7
Department of Pediatrics, University Medical Center Eppendorf, 20246 Hamburg, Germany.
8
Pediatric Neurology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 9112001; Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 9112001.
9
Department of Biochemistry and Genetics, University Hospital, 49933 Angers Cedex 9, France; Equipe MitoLab, CNRS UMR 6015, Inserm U1083, Institut MitoVasc of Angers, CHU Bât IRIS/IBS, Rue des Capucins, 49933 Angers Cedex, France.
10
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
11
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
12
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
13
Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technical University of Munich, 81675 Munich, Germany.
14
Clinical Genetics, Specially for Children, Austin, TX 78723, USA.
15
Valley Hospital, Ridgewood, NJ, USA.
16
Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
17
Division of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; Clinical Genetics, Children's Hospital Colorado, Aurora, CO, USA.
18
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's NHS Foundation Trust, B15 2TG Birmingham, UK.
19
Department of Pediatric Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
20
Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, USA.
21
Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 9112001; Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 9112001.
22
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Undiagnosed Disease Program at the University Medical Center Hamburg-Eppendorf (UDP-UKE), Martinistraße 52, 20246 Hamburg, Germany.
23
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Baylor Genetics Laboratories, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
24
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: kreienkamp@uke.de.

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.

PMID:
29100085
PMCID:
PMC5673606
DOI:
10.1016/j.ajhg.2017.09.014
[Indexed for MEDLINE]
Free PMC Article

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