期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 100, 期 2, 页码 334-342出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2016.12.014
关键词
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资金
- National Institute for Health Research (NIHR)
- Biomedical Research Centre (BRC) at Moor fields Eye Hospital
- UCL Institute of Ophthalmology
- RP Fighting Blindness
- Fight for Sight UK
- Moorfields Eye Hospital Special Trustees
- Foundation Fighting Blindness - USA
- NIHR Bioresource Rare Disease
- Wellcome Trust
- Cambridge Biomedical Research Centre
- BBSRC [BB/N001133/1, BB/N014855/1, BB/L007584/1, BB/J015032/1] Funding Source: UKRI
- MRC [MR/K023489/1, G0600237, MR/M009203/1, MC_EX_MR/M009203/1, MC_PC_14089] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/N014855/1, BB/N001133/1, BB/L007584/1, BB/J015032/1] Funding Source: researchfish
- Fight for Sight [1846/1847, 1740/41] Funding Source: researchfish
- Medical Research Council [G0900098, MC_PC_14089, MR/K023489/1, MC_EX_MR/M009203/1, 1125070, MR/M009203/1, G0600237, MR/K006584/1] Funding Source: researchfish
- National Institute for Health Research [ACF-2013-06-009, NF-SI-0512-10113, NF-SI-0513-10151, CL-2017-06-001] Funding Source: researchfish
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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