Increased Plasma cGMP in a Family With Autosomal Recessive Retinitis Pigmentosa Due to Homozygous Mutations in the <i>PDE6A</i> Gene

Kjellström, Ulrika; Veiga‐Crespo, Patricia; Andréasson, Sten; Ekström, Per

doi:10.1167/iovs.16-19861

Cited by 8 publications

(21 citation statements)

References 65 publications

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“…Several of the 76 CpGs from the discovery study have previously been reported to show differential methylation in association with risk for T2D, obesity, associated cardiometabolic diseases, or aging. These include the top-ranked cg09109411, which is localized to PDE6A, encoding the cyclic-GMP-specific phosphodiesterase 6A α subunit, involved in transmission and amplification of the visual signal (37). This CpG was previously reported to show decreased methylation in association with obesity shown in healthy young adult female and male monozygotic twin pairs discordant for BMI (n = 30 twin pairs) (38).…”

Section: Discussionmentioning

confidence: 99%

Gestational diabetes and maternal obesity are associated with epigenome-wide methylation changes in children

et al. 2018

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Offspring of women with gestational diabetes mellitus (GDM) are at increased risk of developing metabolic disease, potentially mediated by epigenetic mechanisms. We recruited 608 GDM and 626 control offspring from the Danish National Birth Cohort, aged between 9 and 16 years. DNA methylation profiles were measured in peripheral blood of 93 GDM offspring and 95 controls using the Illumina HumanMethylation450 BeadChip. Pyrosequencing was performed for validation/replication of putative GDM-associated, differentially methylated CpGs in additional 905 offspring (462 GDM, 444 control offspring). We identified 76 differentially methylated CpGs in GDM offspring compared with controls in the discovery cohort (FDR, P < 0.05). Adjusting for offspring BMI did not affect the association between methylation levels and GDM status for any of the 76 CpGs. Most of these epigenetic changes were due to confounding by maternal prepregnancy BMI; however, 13 methylation changes were independently associated with maternal GDM. Three prepregnancy BMI-associated CpGs (cg00992687 and cg09452568 of ESM1 and cg14328641 of MS4A3) were validated in the replication cohort, while cg09109411 (PDE6A) was found to be associated with GDM status. The identified methylation changes may reflect developmental programming of organ disease mechanisms and/or may serve as disease biomarkers.

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Section: Discussionmentioning

confidence: 99%

Gestational diabetes and maternal obesity are associated with epigenome-wide methylation changes in children

et al. 2018

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“…These patients are characterized by primary degeneration of the rod photoreceptor cells and subsequent degeneration of the cone photoreceptor cells. 5 , 6 , 7 Two school-aged cases with PDE6A variants have been reported as early-onset RP. 5 , 18 In one case, a 5-year-old child with the homozygous p.R653X variant (the same variant in our case) exhibited a loss of visual fields, diminished visual acuity, a typical fundus appearance of RP and reduced a-wave and b-wave amplitudes in ERG, although there were no ophthalmic images described.…”

Section: Discussionmentioning

confidence: 99%

“…These characteristics include onset in early childhood, retinal degeneration with bone spicule pigmentation from mid-peripheral to peripheral retina, attenuation of peripheral retinal vessels, distinguished ERG responses of both rod and cone function, and a severely constricted visual field until reaching their 20s–30s. 6 , 7 , 19 , 20 , 21 , 22 Furthermore, macula involvements, which are often accompanied by macular edema and atrophy, have been reported in most of these types of cases. These involvements are observed until subjects reach their 20s–30s, with further progression noted in some older patients.…”

Section: Discussionmentioning

confidence: 99%

“… 3 , 4 The PDE6A gene encodes the alpha subunit of the cyclic guanosine monophosphate phosphodiesterase, with dysfunction of the PDE6A protein primarily affecting the rod photoreceptor cells and secondarily affecting the cone photoreceptor cells. 5 , 6 , 7 A previous study has reported that the prevalence of PDE6A variants was about 3–4% in arRP patients in North America. 8 In contrast, a large-scale molecular genetic analysis of Japanese RP patients reports that none of the RP was caused by PDE6A variants, 9 , 10 , 11 which suggests that PDE6A -related arRP appears to be rare in the Japanese population.…”

Section: Introductionmentioning

confidence: 99%

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Clinical findings of end-stage retinitis pigmentosa with a homozygous PDE6A variant (p.R653X)

Mizobuchi

Katagiri

Hayashi

et al. 2019

American Journal of Ophthalmology Case Reports

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PurposeTo report clinical and genetic features of a Japanese patient with end-stage retinitis pigmentosa (RP) caused by a homozygous PDE6A variant.MethodsWe performed comprehensive ophthalmic examinations. Whole exome sequencing analysis was used to investigate the RP patient with parental consanguinity. The pedigree included 4 RP patients in the two generations, which suggests presumed pseudo-autosomal dominant inheritance.ResultsA PDE6A variant (p.R653X) was identified to be homozygous and disease-causing in the patient. Homozygosity mapping revealed the homozygous region including the variant and confirmation of autosomal recessive inheritance. The patient reported night blindness at 4 years of age and exhibited typical RP fundus appearance with macula involvement during the follow-up period from at the age of 52–69 years. At the age of 52, the patient exhibited a loss of visual acuity and had severely constricted visual fields, with a further gradual deterioration of her vision until she was 69 years old. At the age of 69, funduscopy showed severe chorioretinal degeneration in the area from the posterior pole to the peripheral retina.Conclusions and ImportanceThis is the first report that the PDE6A variant (p.R653X) has been identified as one of the causes of autosomal recessive RP in the Japanese population. Longitudinal natural history/end-stage findings demonstrated early-onset and a severe RP phenotype with macula involvement when the patient was in her 50s and severe chorioretinal degenerations in her late 60s.

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“…RP is both clinically and genetically heterogeneous, inherited following Mendelian inheritance patterns. The most common RP inheritance pattern is autosomal recessive (50–60%), followed by autosomal dominant (30–40%), and X-linked trait (5–15%) [ 1 , 8 , 9 ]. Additionally, mitochondrial, de novo , and digenic mutations are reported in rare cases [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel mutation in the ABCA4 gene in a Chinese family with retinitis pigmentosa using exome sequencing

Huang

Yuan

et al. 2018

Bioscience Reports

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Retinitis pigmentosa (RP) is a group of hereditary, degenerative retinal disorders characterized by progressive retinal dysfunction, outer retina cell loss, and retinal tissue atrophy. It eventually leads to tunnel vision and legal or total blindness. Here, we aimed to reveal the causal gene and mutation contributing to the development of autosomal recessive RP (arRP) in a consanguineous family. A novel homozygous mutation, c.4845delT (p.K1616Rfs*46), in the ATP-binding cassette subfamily A member 4 gene (ABCA4) was identified. It may reduce ABCA4 protein activity, leading to progressive degeneration of both rod and cone photoreceptors. The study extends the arRP genotypic spectrum and confirms a genotype–phenotype relationship. The present study may also disclose some new clues for RP genetic causes and pathogenesis, as well as clinical and genetic diagnosis. The research findings may contribute to improvement in clinical care, therapy, genetic screening, and counseling.

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Increased Plasma cGMP in a Family With Autosomal Recessive Retinitis Pigmentosa Due to Homozygous Mutations in the PDE6A Gene

Cited by 8 publications

References 65 publications

Gestational diabetes and maternal obesity are associated with epigenome-wide methylation changes in children

Gestational diabetes and maternal obesity are associated with epigenome-wide methylation changes in children

Clinical findings of end-stage retinitis pigmentosa with a homozygous PDE6A variant (p.R653X)

Identification of a novel mutation in the ABCA4 gene in a Chinese family with retinitis pigmentosa using exome sequencing

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