Whole Exome Sequencing Reveals GUCY2D as a Major Gene Associated With Cone and Cone-Rod Dystrophy in Israel

Lazar, Csilla H.; Mutsuddi, Mousumi; Kimchi, Adva; Zelinger, Lina; Mizrahi-Meissonnier, Liliana; Marks-Ohana, Devorah; Boleda, Alexis; Ratnapriya, Rinki; Sharon, Dror; Swaroop, Anand; Banin, Eyal

doi:10.1167/iovs.14-15647

Cited by 30 publications

(26 citation statements)

References 46 publications

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“…Nonetheless, the detection rate is still much lower than the reported 83% of European families interrogated using a similar approach. 43 Other population groups investigated in a comparable manner include Saudi Arabian, 44 Chinese, 45 Thai, 46 and Israeli, 22,47 with detection rates ranging from 49% to 83% and the number of analyzed genes ranging from 60 to 226.…”

Section: Discussionmentioning

confidence: 99%

“…An increased number of mutations are now being identified in different populations using high-throughput methods such as whole-exome sequencing (WES). 21,22 Improved molecular diagnosis in patients is important, given the number of clinical trials and treatments currently under investigation for this group of disorders. 23 We therefore resorted to a comprehensive WES approach, followed by targeted analysis of all reported IRD genes, toward understanding the genetic architecture of IRD in the indigenous SA population.…”

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confidence: 99%

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Molecular Diagnosis of Inherited Retinal Diseases in Indigenous African Populations by Whole-Exome Sequencing

Roberts

Ratnapriya

Plessis

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PurposeA majority of genes associated with inherited retinal diseases (IRDs) have been identified in patients of European origin. Indigenous African populations exhibit rich genomic diversity, and evaluation of reported genetic mutations has yielded low returns so far. Our goal was to perform whole-exome sequencing (WES) to examine variants in known IRD genes in underrepresented African cohorts.MethodsWhole-exome sequencing was performed on 56 samples from 16 families with diverse IRD phenotypes that had remained undiagnosed after screening for known mutations using genotyping-based microarrays (Asper Ophthalmics). Variants in reported IRD genes were identified using WES and validated by Sanger sequencing. Custom TaqMan assays were used to screen for identified mutations in 193 unrelated indigenous Africans with IRDs.ResultsA total of 3494 variants were identified in 217 known IRD genes, leading to the identification of seven different mutations (including six novel) in six genes (RHO, PRPF3, PRPF31, ABCA4, CERKL, and PDE6B) in six distinct families. TaqMan screening in additional probands revealed identical homozygous CERKL and PDE6B variants in four more patients.ConclusionsThis is the first report of WES of patients with IRDs in indigenous African populations. Our study identified genetic defects in almost 40% of the families analyzed, significantly enhancing the molecular diagnosis of IRD in South Africa. Thus, WES of understudied cohorts seems to present an effective strategy for determining novel mutations in heterogeneous retinal diseases.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Molecular Diagnosis of Inherited Retinal Diseases in Indigenous African Populations by Whole-Exome Sequencing

Roberts

Ratnapriya

Plessis

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…Among the genes linked to CORD6 in multiple genetic studies (34,45,51,52), GUCY2D coding for a human RetGC1 has been found most frequently affected by substitutions in codon 838 replacing , were shown to cause a prominent shift in Ca 2ϩ sensitivity of the cyclase regulation by GCAP1 when heterologously expressed in cultured HEK293 (44 -46). However, the physiological effects of the Arg 838 substitutions in RetGC1 have not been demonstrated in mammalian photoreceptors.…”

Section: The Arg 838 Mutation In Retgc1 Alters Physiology Of Photorecmentioning

confidence: 99%

The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice

Dizhoor

Peshenko

2016

Journal of Biological Chemistry

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Edited by Roger ColbranSubstitutions of Arg 838 in the dimerization domain of a human retinal membrane guanylyl cyclase 1 (RetGC1) linked to autosomal dominant cone-rod degeneration type 6 (CORD6) change RetGC1 regulation in vitro by Ca 2؉ . In addition, we find that R838S substitution makes RetGC1 less sensitive to inhibition by retinal degeneration-3 protein (RD3). We selectively expressed human R838S RetGC1 in mouse rods and documented the decline in rod vision and rod survival. To verify that changes in rods were specifically caused by the CORD6 mutation, we used for comparison cones, which in the same mice did not express R838S RetGC1 from the transgenic construct. The R838S RetGC1 expression in rod outer segments reduced inhibition of cGMP production in the transgenic mouse retinas at the free calcium concentrations typical for dark-adapted rods. The transgenic mice demonstrated early-onset and rapidly progressed with age decline in visual responses from the targeted rods, in contrast to the longer lasting preservation of function in the non-targeted cones. The decline in rod function in the retina resulted from a progressive degeneration of rods between 1 and 6 months of age, with the severity and pace of the degeneration consistent with the extent to which the Ca 2؉ sensitivity of the retinal cGMP production was affected. Our study presents a new experimental model for exploring cellular mechanisms of the CORD6-related photoreceptor death. This mouse model provides the first direct biochemical and physiological in vivo evidence for the Arg 838 substitutions in RetGC1 being the culprit behind the pathogenesis of the CORD6 congenital blindness.Retinal membrane guanylyl cyclase (RetGC) 2 is one of the key enzymes in vertebrate visual signaling. Rods and cones respond to light by closing cGMP-gated plasma membrane channels in the outer segment as cGMP becomes hydrolyzed by phosphodiesterase PDE6 and then re-open the channels, after PDE6 activity becomes quenched and cGMP becomes re-synthesized by RetGC (1-5). Two RetGC isozymes expressed in photoreceptors, , bind calcium-sensor proteins, GCAPs (7-12), which decelerate the cyclase activity at high intracellular calcium concentrations in the dark and accelerate it in the light, when the influx of calcium through the cGMP-gated channels is shut off (13)(14)(15)(16)(17)(18)(19). RetGC also binds retinal degeneration 3 (RD3) protein (20 -21), which prevents cyclase activation by GCAPs (22-23) and promotes accumulation of RetGC1 in the outer segments (21,24,25). RetGC1 (human gene GUCY2D) accounts for most of the cGMP synthesis in mammalian photoreceptors (26,27), therefore mutations in RetGC1 that disable the cyclase activity (28 -33) cause recessive blindness at birth, Leber congenital amaurosis type 1 (LCA1) (33), mostly a non-degenerative or partially degenerative (31, 32) loss-of-function hereditary retinal disease. Different from the LCA1 type of severe congenital blindness linked to the RetGC1 gene, cone-rod dystrophy type 6 (CORD6), is a progressive ear...

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“…1,2,[5][6][7][8] The previous studies have identified mutations in 17 patients from nine families. The numbers for reports, cases, and mutations are summarized in Table 2.…”

Section: Comparative Analysis Of the Literature Datamentioning

confidence: 99%

“…There have been only six previous reports describing C8orf37 mutations, 1,2,[5][6][7][8] and no clear genotype-phenotype correlations have been described so far. The present study examined a consanguineous family of Moroccan origin including two siblings with early-onset CRD.…”

Section: Introductionmentioning

confidence: 99%

A novelC8orf37splice mutation and genotype-phenotype correlation for cone-rod dystrophy

Rahner

Nuernberg

Finis

et al. 2016

Ophthalmic Genetics

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Whole Exome Sequencing Reveals GUCY2D as a Major Gene Associated With Cone and Cone-Rod Dystrophy in Israel

Cited by 30 publications

References 46 publications

Molecular Diagnosis of Inherited Retinal Diseases in Indigenous African Populations by Whole-Exome Sequencing

Molecular Diagnosis of Inherited Retinal Diseases in Indigenous African Populations by Whole-Exome Sequencing

The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice

A novelC8orf37splice mutation and genotype-phenotype correlation for cone-rod dystrophy

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