Vitamin C modulates glutamate transport and NMDA receptor function in the retina

et al. 2020

BMC Med Genet

Background: Autosomal recessive bestrophinopathy (ARB) is a retinal degenerative disorder caused by BEST1 mutations with autosomal recessive inheritance. We aim to map a comprehensive genomic and metabolomic profile of a consanguineous Chinese family with ARB. Methods: Ophthalmic examinations were performed on the affected patients with ARB. The proband was screened for potential causative mutations in a panel with 256 known retinal disease genes by using target capture sequencing. The related mutation was further validated and segregated in the family members by Sanger sequencing. In silico prediction tools were used for pathogenicity assessment. A UHPLC-MS/MS metabolomic analysis was performed to explore the disease-associated metabolic feature. Results: The affected patients from this family were characterized by low vision, the presence of subretinal fluid, macular edema, and hyperopia with coincidental angle closure. DNA sequencing identified a novel missense mutation in the BEST1 gene c.646G > A (p.Val216Ile) of the proband. Sanger sequencing further confirmed the mutation. The missense mutation was co-segregation across the pedigree and predicted to be deleterious by SIFT (0.017). The blood metabolic profiles were highly similar among all family members probably because of the same lifestyle, habitat and genomic background. However, ARB patients presented a significant deregulation of metabolites, such as citric acid, L-Threonic acid, and eicosapentaenoic acid. Conclusions: We identified a novel disease-associated variant in the BEST1 gene as well as a disease-specific metabolic feature in familial ARB. Our findings helped improve the understanding of ARB mechanisms.

Section: Discussionmentioning

confidence: 99%

Familial autosomal recessive bestrophinopathy: identification of a novel variant in BEST1 gene and the specific metabolomic profile

et al. 2020

BMC Med Genet

“…It is uptaken by human RPE cells as a preferred nutrient [15] and its buffer is widely used in the in vivo retina experiments. L-threonate acid is a metabolite of ascorbate (vitamin C), which is highly concentrated in the retina and plays an important role in physiological function and protects RPE from oxidant injury [16,17]…”

Section: Discussionmentioning

confidence: 99%

Familial autosomal recessive bestrophinopathy: identification of a novel variant in BEST1 gene and the specific metabolomic profile

et al. 2019

Preprint

BackgroundAutosomal recessive bestrophinopathy (ARB) is a retinal degenerative disorder caused by BEST1 mutations with autosomal recessive inheritance. We aim to map a comprehensive genomic and metabolic profile of a consanguineous Chinese family with ARB.MethodsOphthalmic examinations were performed on affected patients with ARB. Target capture sequencing was performed to screen causative mutations in 256 known retinal disease genes and Sanger sequencing were used for verification. A UHPLC-MS/MS metabolomic analysis was performed to explore the disease-associated metabolic feature.ResultsAffected patients from this family were characterized by low vision, the presence of subretinal fluid, macular edema, and hyperopia with coincidental angle closure. DNA sequencing identified a novel missense mutation in BEST1 gene (chr11:61725867G>A) of the proband. Sanger sequencing further confirmed the mutation. The blood metabolic profiles were highly similar among all family members probably due to the same life style, habitats and genomic background. However, ARB patients presented significant deregulation of metabolites such as Citric acid, L-Threonic acid, Eicosapentaenoic acid.Conclusions We identified a novel disease-associated variant in BEST1 gene as well as a disease-specific metabolic feature in familial ARB. The findings improved the understanding of mechanisms of ARB and provided a potential therapeutic strategy with application of metabolomics.

“…It is uptook by human RPE cells as a preferred nutrient [15] and its buffer is widely used in the in vivo retina experiments. L-threonate acid is a metabolite of ascorbate (vitamin C), which is highly concentrated in the retina and plays an important role in physiological function and protects RPE from oxidant injury [16,17]. A systemic review including 6150 participants demonstrated that antioxidant vitamin could slow the progression of age-related macular degeneration [18].…”

Section: Discussionmentioning

confidence: 99%

Familial autosomal recessive bestrophinopathy: identification of a novel variant in BEST1 gene and the specific metabolomic profile

et al. 2019

Preprint

Background Autosomal recessive bestrophinopathy (ARB) is a retinal degenerative disorder caused by BEST1 mutations with autosomal recessive inheritance. We aim to map a comprehensive genomic and metabolic profile of a consanguineous Chinese family with ARB.Methods Ophthalmic examinations were performed on affected patients with ARB. Target capture sequencing was performed to screen causative mutations in 256 known retinal disease genes and Sanger sequencing were used for verification. A UHPLC-MS/MS metabolomic analysis was performed to explore the disease-associated metabolic feature.Results Affected patients from this family are characterized by low vision, the presence of subretinal fluid, macular edema, and hyperopia with coincidental angle closure. DNA sequencing identified a novel missense mutation in BEST1 gene (chr11:61725867G>A) of the proband. Sanger sequencing further confirmed the mutation. The blood metabolic profiles were very similar among all family members probably due to the same life style, habitats and genomic background. However, ARB patients presented significant deregulation of metabolites such as Citric acid, L-Threonic acid, Eicosapentaenoic acid.Conclusions We identified a novel disease-associated variant in BEST1 gene as well as the disease-specific metabolic feature in familial ARB. The findings improved the understanding of mechanisms of ARB and provided a potential therapeutic strategy with application of metabolomics.