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

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.Asp540Glyfs63), 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.

Apical polarity proteins recruit the RhoGEF Cysts to promote junctional myosin assembly

“…In contrast, we did not detect genetic or biochemical interactions between Cyst and Yrt in Drosophila. Recently, ARHGEF18, the human orthologue of p114RhoGEF, was identified as a gene associated with retinal degeneration (Arno et al, 2017), and a fish orthologue is required to maintain epithelial integrity of the retina (Herder et al, 2013). ARHGEF18 mutant retinal defects closely resemble those found in patients carrying mutations in the crb homologue CRB1 (Arno et al, 2017).…”

The RhoGEF Cysts couples apical polarity proteins to Rho and myosin activity at adherens junctions

“…In contrast, we did not detect genetic or biochemical interactions between Cyst and Yrt in Drosophila. Recently, ARHGEF18, the human ortholog of p114RhoGEF, was identified as a gene associated with retinal degeneration (Arno et al, 2017), and a fish ortholog is required to maintain epithelial integrity of the retina (Herder et al, 2013). ARHGEF18 mutant retinal defects closely resemble those found in patients carrying mutations in the crb homolog CRB1 (Arno et al, 2017).…”

“…Recently, ARHGEF18, the human ortholog of p114RhoGEF, was identified as a gene associated with retinal degeneration (Arno et al, 2017), and a fish ortholog is required to maintain epithelial integrity of the retina (Herder et al, 2013). ARHGEF18 mutant retinal defects closely resemble those found in patients carrying mutations in the crb homolog CRB1 (Arno et al, 2017). We conclude that the function of Cyst and p114RhoGEF/ARHGEF18 in coupling apical polarity proteins to junctional Rho activity and actomyosin function is conserved between flies and mammals and likely contributes to retinal health in humans, although some of the molecular interactions may have shifted in relative importance.…”

Expression of novel “LOCGEF” isoforms of ARHGEF18 in eosinophils

“…5 Exogenous expression of the p114 isoform also demonstrated its role in organizing actomyosin cytoskeletal components, thereby regulating stress fiber formation 1,5 and maintaining neuro-epithelial apico-basal polarity. 4 Arno et al 12 recently reported 5 mutations in ARHGEF18 that are associated with retinal dystrophy in humans.…”