title: 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.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.
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Arno
authors.affiliation: Department of Haematology, University of Cambridge NHS Blood and Transplant Centre, Cambridge CB2 0PT, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
authors.forename: Keren J
authors.initials: KJ
authors.lastname: Carss
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hull
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Ceniz
authors.initials: C
authors.lastname: Zihni
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Robson
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fiorentino
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hardcastle
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Graham E
authors.initials: GE
authors.lastname: Holder
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.affiliation: University College London Genetics Institute, London WC1E 6BT, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK; Ophthalmology Department, UCSF School of Medicine, Koret Vision Centre, San Francisco, CA 94133-0644, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Karl
authors.initials: K
authors.lastname: Matter
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Balda
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK. Electronic address: andrew.webster@ucl.ac.uk.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
mesh_terms: D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D016764:Cell Polarity; D004847:Epithelial Cells / Q000378:metabolism*; D059472:Exome; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D012160:Retina / Q000378:metabolism; D012162:Retinal Degeneration / Q000175:diagnosis / Q000235:genetics*; D058499:Retinal Dystrophies / Q000235:genetics; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C577230:ARHGEF18 protein, human; C448939:CRB1 protein, human; D005136:Eye Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein
keywords: ARHGEF18; apicobasal polarity; inherited retinal dystrophy; p114RhoGEF; retinal degeneration; retinitis pigmentosa