TY - JOUR
T1 - Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration
AU - Arno, Gavin
AU - Carss, Keren J.
AU - Hull, Sarah
AU - Zihni, Ceniz
AU - Robson, Anthony G.
AU - Fiorentino, Alessia
AU - Hardcastle, Alison J.
AU - Holder, Graham E.
AU - Cheetham, Michael E.
AU - Plagnol, Vincent
AU - Moore, Anthony T.
AU - Raymond, F. Lucy
AU - Matter, Karl
AU - Balda, Maria S.
AU - UK Inherited Retinal Dis
AU - Henskens, Yvonne
AU - NIHR-BioResource Rare Dis
AU - Webster, Andrew R.
PY - 2017/2/2
Y1 - 2017/2/2
N2 - 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.G1u878*), and c.2738_2761de1 (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 Arligef18 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.
AB - 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.G1u878*), and c.2738_2761de1 (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 Arligef18 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.
KW - INTEGRATIVE GENOMICS VIEWER
KW - NUCLEOTIDE EXCHANGE FACTOR
KW - CELL FEATURES
KW - MOSAIC EYES
KW - OKO-MEDUZY
KW - CRB1
KW - PROTEIN
KW - MORPHOGENESIS
KW - RHOA
KW - ACTIVATION
U2 - 10.1016/j.ajhg.2016.12.014
DO - 10.1016/j.ajhg.2016.12.014
M3 - Article
C2 - 28132693
SN - 0002-9297
VL - 100
SP - 334
EP - 342
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -