iSyTE:IntegratedSystemsTool forEye Gene Discovery

Lachke, Salil A.; Ho, Joshua W. K.; Kryukov, Gregory V.; O’Connell, Daniel J.; Aboukhalil, Anton; Bulyk, Martha L.; Park, Peter J.; Maas, Richard L.

doi:10.1167/iovs.11-8839

Cited by 90 publications

(159 citation statements)

References 53 publications

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“…Caprin2 is involved in erythroblast terminal differentiation, processes with extensive similarities to lens cell development (19). Interestingly, Caprin2 is expressed at higher levels upon lens development (20) and is predicted to be a cataract-associated gene (21). Mass spectrometry indicated lower levels of Tdrd7 and Caprin2 in K6W-Ub lenses (Table S3).…”

Section: Resultsmentioning

confidence: 99%

Altered ubiquitin causes perturbed calcium homeostasis, hyperactivation of calpain, dysregulated differentiation, and cataract

Liu

Lyu

Chin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Although the ocular lens shares many features with other tissues, it is unique in that it retains its cells throughout life, making it ideal for studies of differentiation/development. Precipitation of proteins results in lens opacification, or cataract, the major blinding disease. Lysines on ubiquitin (Ub) determine fates of Ub-protein substrates. Information regarding ubiquitin proteasome systems (UPSs), specifically of K6 in ubiquitin, is undeveloped. We expressed in the lens a mutant Ub containing a K6W substitution (K6W-Ub). Protein profiles of lenses that express wild-type ubiquitin (WT-Ub) or K6W-Ub differ by only ∼2%. Despite these quantitatively minor differences, in K6W-Ub lenses and multiple model systems we observed a fourfold Ca2+ elevation and hyperactivation of calpain in the core of the lens, as well as calpain-associated fragmentation of critical lens proteins including Filensin, Fodrin, Vimentin, β-Crystallin, Caprin family member 2, and tudor domain containing 7. Truncations can be cataractogenic. Additionally, we observed accumulation of gap junction Connexin43, and diminished Connexin46 levels in vivo and in vitro. These findings suggest that mutation of Ub K6 alters UPS function, perturbs gap junction function, resulting in Ca2+ elevation, hyperactivation of calpain, and associated cleavage of substrates, culminating in developmental defects and a cataractous lens. The data show previously unidentified connections between UPS and calpain-based degradative systems and advance our understanding of roles for Ub K6 in eye development. They also inform about new approaches to delay cataract and other protein precipitation diseases.

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Section: Resultsmentioning

confidence: 99%

Altered ubiquitin causes perturbed calcium homeostasis, hyperactivation of calpain, dysregulated differentiation, and cataract

Liu

Lyu

Chin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…26 Although the splicing mutation is predicted to completely abolish the consensus donor site, we were unable to confirm this experimentally due to apparent lack of expression in blood. This enzyme catalyzes the nicotinamide adenine dinucleotide phosphate-oxidase-dependent reduction of glycogen-derived 1,5-anhydro-D-fructose (AF) to 1,5-anhydro-D-glucitol (AG).…”

Section: Discussionmentioning

confidence: 90%

Genomic analysis of pediatric cataract in Saudi Arabia reveals novel candidate disease genes

Aldahmesh

Khan

Mohamed

et al. 2012

Genetics in Medicine

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dominant manner. In addition, several novel candidate genes (MFSD6L, AKR1E2, RNLS, and CYP51A1) were identified.conclusion: Pediatric cataract is typically a genetic disease, usually autosomal recessive, in Saudi Arabia. Although defining a specific cataract phenotype can sometimes predict the genetic cause, genomic analysis is often required to unravel the causative mutation given the marked genetic heterogeneity. The identified novel candidate genes require independent confirmation in future studies. 2012:14(12):955-962 Genet Med

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“…The lensenrichment score for a gene is defined as the measure of its fold difference in expression between the lens and the whole embryonic body reference at P<0.05. Lens-enrichment scores change as lens differentiation proceeds from the lens pit at E10.5 to the early lens at E12.5, potentially indicating that a gene exhibits enriched expression in differentiating LFs (Lachke et al, 2012). Fig.…”

Section: Prox1 Cko Presumptive Lfs Appropriately Decrease Expression mentioning

confidence: 97%

Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression

Audette

Anand

et al. 2015

Development

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Lens epithelial cells differentiate into lens fibers (LFs) in response to a fibroblast growth factor (FGF) gradient. This cell fate decision requires the transcription factor Prox1, which has been hypothesized to promote cell cycle exit in differentiating LF cells. However, we find that conditional deletion of Prox1 from mouse lenses results in a failure in LF differentiation despite maintenance of normal cell cycle exit. Instead, RNA-seq demonstrated that Prox1 functions as a global regulator of LF cell gene expression. Intriguingly, Prox1 also controls the expression of fibroblast growth factor receptors (FGFRs) and can bind to their promoters, correlating with decreased downstream signaling through MAPK and AKT in Prox1 mutant lenses. Further, culturing rat lens explants in FGF increased their expression of Prox1, and this was attenuated by the addition of inhibitors of MAPK. Together, these results describe a novel feedback loop required for lens differentiation and morphogenesis, whereby Prox1 and FGFR signaling interact to mediate LF differentiation in response to FGF.

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iSyTE:IntegratedSystemsTool forEye Gene Discovery

Abstract: iSyTE is a publicly available Web resource that can be used to prioritize candidate genes within mapped genomic intervals associated with congenital cataract for further investigation. Extension of this approach to other ocular tissue components will facilitate eye disease gene discovery.

Cited by 90 publications

References 53 publications

Altered ubiquitin causes perturbed calcium homeostasis, hyperactivation of calpain, dysregulated differentiation, and cataract

Altered ubiquitin causes perturbed calcium homeostasis, hyperactivation of calpain, dysregulated differentiation, and cataract

Genomic analysis of pediatric cataract in Saudi Arabia reveals novel candidate disease genes

Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression

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