Challenges confronting precision medicine in the context of inherited retinal disorders

Chiang, John; Gorin, Michael B.

doi:10.1080/23808993.2016.1152159

Cited by 5 publications

(6 citation statements)

References 62 publications

(65 reference statements)

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“…Determining mutant function rapidly and accurately has become increasingly important with the rise of whole genome sequencing, and the ever-expanding rise in gene mutations with an unknown impact on human health. Rhodopsin mutations linked to inherited retinal disease have been used as examples of how many gene mutations discovered in patients are rarely characterized, and that the molecular basis for pathology is poorly understood (Davies 2014;Chiang and Gorin 2016). Animal models and traditional in vitro assays provide detailed information, but they have not kept pace with the hundreds (.350) of rhodopsin mutations identified to date.…”

Section: Characterizing Novel Rhodopsin Mutations With Yeastmentioning

confidence: 99%

Coupling of Human Rhodopsin to a Yeast Signaling Pathway Enables Characterization of Mutations Associated with Retinal Disease

et al. 2018

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G protein-coupled receptors (GPCRs) are crucial sensors of extracellular signals in eukaryotes, with multiple GPCR mutations linked to human diseases. With the growing number of sequenced human genomes, determining the pathogenicity of a mutation is challenging, but can be aided by a direct measurement of GPCR-mediated signaling. This is particularly difficult for the visual pigment rhodopsin-a GPCR activated by light-for which hundreds of mutations have been linked to inherited degenerative retinal diseases such as retinitis pigmentosa. In this study, we successfully engineered, for the first time, activation by human rhodopsin of the yeast mating pathway, resulting in signaling via a fluorescent reporter. We combine this novel assay for rhodopsin lightdependent activation with studies of subcellular localization, and the upregulation of the unfolded protein response in response to misfolded rhodopsin protein. We use these assays to characterize a panel of rhodopsin mutations with known molecular phenotypes, finding that rhodopsin maintains a similar molecular phenotype in yeast, with some interesting differences. Furthermore, we compare our assays in yeast with clinical phenotypes from patients with novel disease-linked mutations. We demonstrate that our engineered yeast strain can be useful in rhodopsin mutant classification, and in helping to determine the molecular mechanisms underlying their pathogenicity. This approach may also be applied to better understand the clinical relevance of other human GPCR mutations, furthering the use of yeast as a tool for investigating molecular mechanisms relevant to human disease.

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Section: Characterizing Novel Rhodopsin Mutations With Yeastmentioning

confidence: 99%

Coupling of Human Rhodopsin to a Yeast Signaling Pathway Enables Characterization of Mutations Associated with Retinal Disease

et al. 2018

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“…Such identification of ncRNAs from WES could be attributed to the sequencing chemistry or impact of library targeted on intergenic regions, which needs a careful reassessment. With a genetic basis for many Mendelian traits/rare diseases not being clear, there are challenges widely seen towards understanding the emergence of mutations for various phenotypes, viz.penetrance [ 13 ], dominance, age-of-onset [ 14 ] and expressivity [ 15 ], complex genetic and environmental interaction studies, etc. [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Lnc-EPB41-Protein Interactions Associated with Congenital Pouch Colon

Gupta

Tiwari

et al. 2018

Biomolecules

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Congenital Pouch Colon (CPC) is a rare anorectal anomaly common to northwestern India, specifically Rajasthan. Despite efforts to understand the clinical genetic makeup of CPC, no attempt on identifying non-coding RNAs was done. We have earlier reported CPC’s rare variants from whole exome sequencing (WES) across 18 affected samples in a total of 64 subjects. A Smith–Waterman algorithm was used to infer a couple of lncRNAs from WES samples of CPC with predictions from the Noncode database. Further screening and quantification using polymerase chain reaction (PCR), we ascertained interactions using Micro Scale Thermophoresis (MST). We report the role of lnc-EPB41-1-1 shown to be promiscuously interacting with KIF13A substantiating their role in regulation.

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“…; Parfitt et al. ) will be required to discern the most effective treatment (Chiang and Gorin ). Unraveling the genetic etiology of disease in individuals will thus be a prerequisite, and could identify potential candidates for personalized therapies, inform patient management (including diagnostic confirmation, dietary modifications, and reproductive options), and discriminate possible syndromic forms of disease.…”

Section: Introductionmentioning

confidence: 99%

“…[AONs]/translational-read-through-inducing drugs) (Bainbridge et al 2008;Hauswirth et al 2008;Maguire et al 2008;Goldmann et al 2010;Collin et al 2012;Gerard et al 2012;Koenekoop et al 2014;Schwarz et al 2015;Garanto et al 2016;Li et al 2016;Nagel-Wolfrum et al 2016;Parfitt et al 2016) will be required to discern the most effective treatment (Chiang and Gorin 2016). Unraveling the genetic etiology of disease in individuals will thus be a prerequisite, and could identify potential candidates for personalized therapies, inform patient management (including diagnostic confirmation, dietary modifications, and reproductive options), and discriminate possible syndromic forms of disease.…”

Section: Introductionmentioning

confidence: 99%

The genetic profile of Leber congenital amaurosis in an Australian cohort

Thompson

Roach

McLaren

et al. 2017

Molec Gen & Gen Med

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BackgroundLeber congenital amaurosis (LCA) is a severe visual impairment responsible for infantile blindness, representing ~5% of all inherited retinal dystrophies. LCA encompasses a group of heterogeneous disorders, with 24 genes currently implicated in pathogenesis. Such clinical and genetic heterogeneity poses great challenges for treatment, with personalized therapies anticipated to be the best treatment candidates. Unraveling the individual genetic etiology of disease is a prerequisite for personalized therapies, and could identify potential treatment candidates, inform patient management, and discriminate syndromic forms of disease.MethodsWe have genetically analyzed 45 affected and 82 unaffected individuals from 34 unrelated LCA pedigrees using predominantly next‐generation sequencing and Array CGH technology.ResultsWe present the molecular findings for an Australian LCA cohort, sourced from the Australian Inherited Retinal Disease Registry & DNA Bank. CEP290 and GUCY2D mutations, each represent 19% of unrelated LCA cases, followed by NMNAT1 (12%). Genetic subtypes were consistent with other reports, and were resolved in 90% of this cohort.ConclusionThe high resolution rate achieved, equivalent to recent findings using whole exome/genome sequencing, reflects the progression from hypothesis (LCA Panel) to non‐hypothesis (RD Panel) testing and, coupled with Array CGH analysis, is a highly effective first‐tier test for LCA.

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Challenges confronting precision medicine in the context of inherited retinal disorders

Cited by 5 publications

References 62 publications

Coupling of Human Rhodopsin to a Yeast Signaling Pathway Enables Characterization of Mutations Associated with Retinal Disease

Coupling of Human Rhodopsin to a Yeast Signaling Pathway Enables Characterization of Mutations Associated with Retinal Disease

Lnc-EPB41-Protein Interactions Associated with Congenital Pouch Colon

The genetic profile of Leber congenital amaurosis in an Australian cohort

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