Recurrent De Novo Mutations Disturbing the GTP/GDP Binding Pocket of RAB11B Cause Intellectual Disability and a Distinctive Brain Phenotype

Am J Hum Genet. 2017 Nov 2;101(5):824-832. doi: 10.1016/j.ajhg.2017.09.015.

Ideke J C Lamers ¹, Margot R F Reijnders ², Hanka Venselaar ³, Alison Kraus ⁴, DDD Study ⁵, Sandra Jansen ⁶, Bert B A de Vries ⁶, Gunnar Houge ⁷, Gyri Aasland Gradek ⁷, Jieun Seo ⁸, Murim Choi ⁹, Jong-Hee Chae ⁹, Ineke van der Burgt ¹⁰, Rolph Pfundt ¹⁰, Stef J F Letteboer ¹, Sylvia E C van Beersum ¹, Simone Dusseljee ¹, Han G Brunner ¹¹, Dan Doherty ¹², Tjitske Kleefstra ⁶, Ronald Roepman ¹³

Affiliations

1 Department of Human Genetics, and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands.
2 Department of Human Genetics, and Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands. Electronic address: [email protected].
3 Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands.
4 Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, LS7 4SA, UK.
5 Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
6 Department of Human Genetics, and Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands.
7 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, N-5021, Norway.
8 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
9 Department of Pediatrics, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
10 Department of Human Genetics, Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands.
11 Department of Human Genetics, and Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, 6229 ER, the Netherlands.
12 Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, WA 98195, USA.
13 Department of Human Genetics, and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands. Electronic address: [email protected].

PMID: 29106825 DOI: 10.1016/j.ajhg.2017.09.015

Abstract

The Rab GTPase family comprises ∼70 GTP-binding proteins, functioning in vesicle formation, transport and fusion. They are activated by a conformational change induced by GTP-binding, allowing interactions with downstream effectors. Here, we report five individuals with two recurrent de novo missense mutations in RAB11B; c.64G>A; p.Val22Met in three individuals and c.202G>A; p.Ala68Thr in two individuals. An overlapping neurodevelopmental phenotype, including severe intellectual disability with absent speech, epilepsy, and hypotonia was observed in all affected individuals. Additionally, visual problems, musculoskeletal abnormalities, and microcephaly were present in the majority of cases. Re-evaluation of brain MRI images of four individuals showed a shared distinct brain phenotype, consisting of abnormal white matter (severely decreased volume and abnormal signal), thin corpus callosum, cerebellar vermis hypoplasia, optic nerve hypoplasia and mild ventriculomegaly. To compare the effects of both variants with known inactive GDP- and active GTP-bound RAB11B mutants, we modeled the variants on the three-dimensional protein structure and performed subcellular localization studies. We predicted that both variants alter the GTP/GDP binding pocket and show that they both have localization patterns similar to inactive RAB11B. Evaluation of their influence on the affinity of RAB11B to a series of binary interactors, both effectors and guanine nucleotide exchange factors (GEFs), showed induction of RAB11B binding to the GEF SH3BP5, again similar to inactive RAB11B. In conclusion, we report two recurrent dominant mutations in RAB11B leading to a neurodevelopmental syndrome, likely caused by altered GDP/GTP binding that inactivate the protein and induce GEF binding and protein mislocalization.

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