Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

Am J Hum Genet. 2017 Feb 2;100(2):334-342. doi: 10.1016/j.ajhg.2016.12.014. Epub 2017 Jan 26.

Abstract

Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs∗63), c.1996C>T (p.Arg666∗), c.2632G>T (p.Glu878∗), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.

Keywords: ARHGEF18; apicobasal polarity; inherited retinal dystrophy; p114RhoGEF; retinal degeneration; retinitis pigmentosa.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Alleles
  • Amino Acid Sequence
  • Cell Polarity*
  • Epithelial Cells / metabolism*
  • Exome
  • Eye Proteins / genetics
  • Eye Proteins / metabolism
  • Female
  • Genetic Variation
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Middle Aged
  • Mutation, Missense
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Pedigree
  • Phenotype
  • Retina / metabolism
  • Retinal Degeneration / diagnosis
  • Retinal Degeneration / genetics*
  • Retinal Dystrophies / genetics
  • Rho Guanine Nucleotide Exchange Factors / genetics*
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism

Substances

  • ARHGEF18 protein, human
  • CRB1 protein, human
  • Eye Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Rho Guanine Nucleotide Exchange Factors
  • RHOA protein, human
  • rhoA GTP-Binding Protein

Supplementary concepts

  • Late-Onset Retinal Degeneration