A neurodevelopmental disorder associated with a loss-of-function missense mutation in RAB35

J Biol Chem. 2024 Apr;300(4):107124. doi: 10.1016/j.jbc.2024.107124. Epub 2024 Mar 1.

Abstract

Rab35 (Ras-associated binding protein) is a small GTPase that regulates endosomal membrane trafficking and functions in cell polarity, cytokinesis, and growth factor signaling. Altered Rab35 function contributes to progression of glioblastoma, defects in primary cilia formation, and altered cytokinesis. Here, we report a pediatric patient with global developmental delay, hydrocephalus, a Dandy-Walker malformation, axial hypotonia with peripheral hypertonia, visual problems, and conductive hearing impairment. Exome sequencing identified a homozygous missense variant in the GTPase fold of RAB35 (c.80G>A; p.R27H) as the most likely candidate. Functional analysis of the R27H-Rab35 variant protein revealed enhanced interaction with its guanine-nucleotide exchange factor, DENND1A and decreased interaction with a known effector, MICAL1, indicating that the protein is in an inactive conformation. Cellular expression of the variant drives the activation of Arf6, a small GTPase under negative regulatory control of Rab35. Importantly, variant expression leads to delayed cytokinesis and altered length, number, and Arl13b composition of primary cilia, known factors in neurodevelopmental disease. Our findings provide evidence of altered Rab35 function as a causative factor of a neurodevelopmental disorder.

Keywords: GTPase; Rab35; cytokinesis; neurodevelopmental disorder; primary cilia; recessive mutation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Case Reports

MeSH terms

  • ADP-Ribosylation Factor 6
  • ADP-Ribosylation Factors / genetics
  • ADP-Ribosylation Factors / metabolism
  • Cell Line
  • Cilia / genetics
  • Cilia / metabolism
  • Cilia / pathology
  • Cytokinesis / genetics
  • Female
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Loss of Function Mutation
  • Male
  • Models, Molecular
  • Mutation, Missense*
  • Neurodevelopmental Disorders* / genetics
  • Neurodevelopmental Disorders* / metabolism
  • Neurodevelopmental Disorders* / pathology
  • Pedigree
  • Protein Structure, Tertiary
  • rab GTP-Binding Proteins* / genetics
  • rab GTP-Binding Proteins* / metabolism

Substances

  • ARF6 protein, human
  • RAB35 protein, human