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. Epub 2017 Oct 26.


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.

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Binding Sites
  • Cerebellar Vermis / diagnostic imaging
  • Cerebellar Vermis / metabolism
  • Cerebellar Vermis / pathology
  • Child
  • Child, Preschool
  • Corpus Callosum / diagnostic imaging
  • Corpus Callosum / metabolism
  • Corpus Callosum / pathology
  • Epilepsy / diagnostic imaging
  • Epilepsy / genetics*
  • Epilepsy / pathology
  • Female
  • Gene Expression
  • Guanosine Diphosphate / chemistry
  • Guanosine Diphosphate / metabolism
  • Guanosine Triphosphate / chemistry
  • Guanosine Triphosphate / metabolism
  • Humans
  • Intellectual Disability / diagnostic imaging
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Magnetic Resonance Imaging
  • Male
  • Models, Molecular
  • Muscle Hypotonia / diagnostic imaging
  • Muscle Hypotonia / genetics*
  • Muscle Hypotonia / pathology
  • Mutation*
  • Optic Nerve Diseases / congenital*
  • Optic Nerve Diseases / diagnostic imaging
  • Optic Nerve Diseases / genetics
  • Optic Nerve Diseases / pathology
  • Phenotype
  • Protein Binding
  • White Matter / diagnostic imaging
  • White Matter / metabolism
  • White Matter / pathology
  • rab GTP-Binding Proteins / chemistry
  • rab GTP-Binding Proteins / deficiency
  • rab GTP-Binding Proteins / genetics*


  • Guanosine Diphosphate
  • Guanosine Triphosphate
  • rab11 protein
  • rab GTP-Binding Proteins

Supplementary concepts

  • Optic Nerve Hypoplasia, Bilateral