Adult-Onset Primary Open-Angle Glaucoma Caused by Mutations in Optineurin

Rezaie, Tayebeh; Child, Anne H.; Hitchings, Roger A.; Brice, Glen; Miller, Lauri J.; Coca‐Prados, Miguel; Hèon, Elise; Krupin, Theodore; Ritch, Robert; Kreutzer, Donald L.; Crick, Ronald Pitts; Sarfarazi, Mansoor

doi:10.1126/science.1066901

Cited by 924 publications

(857 citation statements)

References 16 publications

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“…Second, Rab8 interacts with FIP-2 (optineurin) that also modulates cell morphogenesis and links Rab8 to the huntingtin protein (Li et al, 1998;Hattula and Peränen, 2000). Interestingly, mutations in optineurin cause primary open-angle glaucoma (Rezaie et al, 2002). In ADPKD (autosomal dominant polycystic kidney disease) cells loss of polarity is associated with redistribution of Rab8, suggesting a role of Rab8 in controling epithelial polarity (Charron et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

A Rab8-specific GDP/GTP Exchange Factor Is Involved in Actin Remodeling and Polarized Membrane Transport

Hattula

Furuhjelm

Arffman

et al. 2002

MBoC

187

220

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The mechanisms mediating polarized delivery of vesicles to cell surface domains are poorly understood in animal cells. We have previously shown that expression of Rab8 promotes the formation of new cell surface domains through reorganization of actin and microtubules. To unravel the function of Rab8, we used the yeast two-hybrid system to search for potential Rab8-specific activators. We identified a coil-coiled protein (Rabin8), homologous to the rat Rabin3 that stimulated nucleotide exchange on Rab8 but not on Rab3A and Rab5. Furthermore, we show that rat Rabin3 has exchange activity on Rab8 but not on Rab3A, supporting the view that rat Rabin3 is the rat equivalent of human Rabin8. Rabin8 localized to the cortical actin and expression of Rabin8 resulted in remodeling of actin and the formation of polarized cell surface domains. Activation of PKC by phorbol esters enhanced translocation of both Rabin8 and Rab8-specific vesicles to the outer edge of lamellipodial structures. Moreover, coexpression of Rabin8 with dominant negative Rab8 (T22N) redistributes Rabin8 from cortical actin to Rab8-specific vesicles and promotes their polarized transport to cell protrusions. The C-terminal region of Rabin8 plays an essential role in this transport. We propose that Rabin8 is a Rab8-specific activator that is connected to processes that mediate polarized membrane traffic to dynamic cell surface structures.

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Section: Discussionmentioning

confidence: 99%

A Rab8-specific GDP/GTP Exchange Factor Is Involved in Actin Remodeling and Polarized Membrane Transport

Hattula

Furuhjelm

Arffman

et al. 2002

MBoC

187

220

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“…However, these loci and genes may account for only a small proportion of glaucoma seen in the general population. Studies of MYOC and OPTN mutations in the general glaucoma population have shown that they account for 3.4% of open angle glaucoma 65 and up to 15% of NTG, 64 respectively. The association of two intronic OPA1 polymorphisms in the OPA1 gene with normal tension glaucoma (IVS8 þ 4C/T and IVS8 þ 32T/C), 66,67 is of interest since NTG may account for 20-50% of open angle glaucoma.…”

Section: Glaucomamentioning

confidence: 99%

Molecular genetic basis of primary inherited optic neuropathies

Votruba

2004

Eye

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“…11,12 In 1987, Teikari estimated the heritability of chronic open-angle glaucoma to be 13%, based on the Finnish Twin Cohort Study, 13 which supports a polygenic and/or multifactorial mode of transmission. To date, 6 different chromosomal loci have been identified for POAG, 14 -19 including the myocilin (MYOC) 20 and optineurin (OPTN) 21 genes.…”

mentioning

confidence: 99%

Determinants and Heritability of Intraocular Pressure and Cup-to-Disc Ratio in a Defined Older Population

et al. 2005

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Purpose-To investigate the heritability of intraocular pressure (IOP) and cup-to-disc ratio (CDR) in an older well-defined population. Design-Family-based cohort study.Participants-Through the population-based Salisbury Eye Evaluation study, we recruited 726 siblings (mean age, 74.7 years) in 284 sibships.Methods-Intraocular pressure and CDR were measured bilaterally for all participants. The presence or absence of glaucoma was determined by a glacuoma specialist for all probands on the basis of visual field, optic nerve appearance, and history. The heritability of IOP was calculated as twice the residual between-sibling correlation of IOP using linear regression and generalized estimating equations after adjusting for age, gender, mean arterial pressure, race, self-reported diabetes status, and history of systemic steroid use. The heritability of CDR was calculated using the same model and adjustments as above, while also adjusting for IOP.Main Outcome Measures-Heritability and determinants of IOP and CDR, and impact of siblings' glaucoma status on IOP and CDR.Results-We estimated the heritability to be 0.29 (95% confidence interval [CI], 0.12-0.46) for IOP and 0.56 (95% CI, for CDR in this population. Mean IOP in siblings of glaucomatous probands was statistically significantly higher than in siblings of normal probands (mean difference, 1.02 mmHg; P = 0.017). The mean CDR in siblings of glaucomatous probands was 0.07 (or 19%) larger than in siblings of glaucoma suspect referrals (P = 0.045) and siblings of normal probands (P = 0.004).Conclusions-In this elderly population, we found CDR to be highly heritable and IOP to be moderately heritable. On average, siblings of glaucoma patients had higher IOPs and larger CDRs than siblings of nonglaucomatous probands.Primary open-angle glaucoma (POAG) is the second most common cause of blindness in the world 1 and affects approximately 2.2 million Americans. 2 Although the diagnosis of POAG centers on the characteristic excavation and atrophy of the optic nerve head and functional deficit measured by visual field (VF) change, 3 the heritability of intraocular pressure (IOP) and cup-to-disc ratio (CDR) have not been studied extensively thus far, despite the wellestablished role of heredity in POAG. In this study, we estimate the heritability of IOP and CDR from a cohort of sibships recruited through the Salisbury Eye Evaluation study. In addition, we also report the distribution of IOP and CDR among siblings of glaucomatous probands versus siblings of normal probands. Materials and Methods Subjects and General DesignBetween 1993 and 1995, a random sample of potential participants (ages 65 to 84 years) was chosen from the Health Care Financing Administration Medicare database and recruited from Salisbury, located on the Eastern Shore of Maryland, to engage in the population-based Salisbury Eye Evaluation study. 28 The cohort was invited for a follow-up examination including VF testing, optic nerve head imaging, and IOP measurement. All subjects with abnormal scr...

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Adult-Onset Primary Open-Angle Glaucoma Caused by Mutations in Optineurin

Cited by 924 publications

References 16 publications

A Rab8-specific GDP/GTP Exchange Factor Is Involved in Actin Remodeling and Polarized Membrane Transport

A Rab8-specific GDP/GTP Exchange Factor Is Involved in Actin Remodeling and Polarized Membrane Transport

Molecular genetic basis of primary inherited optic neuropathies

Determinants and Heritability of Intraocular Pressure and Cup-to-Disc Ratio in a Defined Older Population

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