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

Gavin Arno, Keren J. Carss, Sarah Hull, Ceniz Zihni, Anthony G. Robson, Alessia Fiorentino, Alison J. Hardcastle, Graham E. Holder, Michael E. Cheetham, Vincent Plagnol, Anthony T. Moore, F. Lucy Raymond, Karl Matter, Maria S. Balda, Andrew R. Webster, UK Inherited Retinal Dis, NIHR Bioresource - Rare Dis, Wendy Erber

Research output: Contribution to journalArticle

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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.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.

Original languageEnglish
Pages (from-to)334-342
Number of pages9
JournalAmerican Journal of Human Genetics
Volume100
Issue number2
DOIs
Publication statusPublished - 2 Feb 2017

Cite this

Arno, Gavin ; Carss, Keren J. ; Hull, Sarah ; Zihni, Ceniz ; Robson, Anthony G. ; Fiorentino, Alessia ; Hardcastle, Alison J. ; Holder, Graham E. ; Cheetham, Michael E. ; Plagnol, Vincent ; Moore, Anthony T. ; Raymond, F. Lucy ; Matter, Karl ; Balda, Maria S. ; Webster, Andrew R. ; UK Inherited Retinal Dis ; NIHR Bioresource - Rare Dis ; Erber, Wendy. / Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration. In: American Journal of Human Genetics. 2017 ; Vol. 100, No. 2. pp. 334-342.
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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.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.",
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author = "Gavin Arno and Carss, {Keren J.} and Sarah Hull and Ceniz Zihni and Robson, {Anthony G.} and Alessia Fiorentino and Hardcastle, {Alison J.} and Holder, {Graham E.} and Cheetham, {Michael E.} and Vincent Plagnol and Moore, {Anthony T.} and Raymond, {F. Lucy} and Karl Matter and Balda, {Maria S.} and Webster, {Andrew R.} and {UK Inherited Retinal Dis} and {NIHR Bioresource - Rare Dis} and Wendy Erber",
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Arno, G, Carss, KJ, Hull, S, Zihni, C, Robson, AG, Fiorentino, A, Hardcastle, AJ, Holder, GE, Cheetham, ME, Plagnol, V, Moore, AT, Raymond, FL, Matter, K, Balda, MS, Webster, AR, UK Inherited Retinal Dis, NIHR Bioresource - Rare Dis & Erber, W 2017, 'Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration' American Journal of Human Genetics, vol. 100, no. 2, pp. 334-342. https://doi.org/10.1016/j.ajhg.2016.12.014

Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration. / Arno, Gavin; Carss, Keren J.; Hull, Sarah; Zihni, Ceniz; Robson, Anthony G.; Fiorentino, Alessia; Hardcastle, Alison J.; Holder, Graham E.; Cheetham, Michael E.; Plagnol, Vincent; Moore, Anthony T.; Raymond, F. Lucy; Matter, Karl; Balda, Maria S.; Webster, Andrew R.; UK Inherited Retinal Dis; NIHR Bioresource - Rare Dis ; Erber, Wendy.

In: American Journal of Human Genetics, Vol. 100, No. 2, 02.02.2017, p. 334-342.

Research output: Contribution to journalArticle

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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 - Webster, Andrew R.

AU - UK Inherited Retinal Dis

AU - NIHR Bioresource - Rare Dis

AU - Erber, Wendy

PY - 2017/2/2

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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.

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KW - NUCLEOTIDE EXCHANGE FACTOR

KW - CELL FEATURES

KW - MOSAIC EYES

KW - OKO-MEDUZY

KW - CRB1

KW - PROTEIN

KW - MORPHOGENESIS

KW - RHOA

KW - ACTIVATION

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DO - 10.1016/j.ajhg.2016.12.014

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SP - 334

EP - 342

JO - The American Journal of Human Genetics

JF - The American Journal of Human Genetics

SN - 0002-9297

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