ArticleHuman mutation2019
In silico and in vivo models for Qatari-specific classical homocystinuria as basis for development of novel therapies.
Article in Human mutation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- Genomic and Structural Investigation of Mutations in Biotinidase (BTD) Gene Deficiency in Greater Middle Eastern Cohort: Insights from Molecular Dynamics Study.Biomedicines · 2025Article
- Unraveling CBS Mutations and Their Clinical Impact in a Chinese Family With Classical Homocystinuria.Molecular genetics & genomic medicine · 2025Article
- Relationship between plasma homocysteine and clinical grading of varicocele.Asian journal of andrology · 2025Article
- Cellular turnover and degradation of the most common missense cystathionine beta-synthase variants causing homocystinuria.Protein science : a publication of the Protein Society · 2024Article
- Genomic Newborn Screening for Pediatric Cancer Predisposition Syndromes: A Holistic Approach.Cancers · 2024Review
- Pathogenic Homocystinuria-Associated T236N Mutation Dramatically Alters the Biochemical Properties of Cystathionine Beta-Synthase Protein.Biomedicines · 2024Article
- Architecture and regulation of filamentous human cystathionine beta-synthase.Nature communications · 2024Article
- Current and Novel Therapeutical Approaches of Classical Homocystinuria in Childhood With Special Focus on Enzyme Replacement Therapy, Liver-Directed Therapy and Gene Therapy.Journal of clinical medicine research · 2023Review
- Mechanism of homocysteine-mediated endothelial injury and its consequences for atherosclerosis.Frontiers in cardiovascular medicine · 2022Review
- Early Diagnosis of Classic Homocystinuria in Kuwait through Newborn Screening: A 6-Year Experience.International journal of neonatal screening · 2021Article
- Review
- Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations.International journal of molecular sciences · 2020Review
- Analysis of the Qatari R336C cystathionine β-synthase protein in mice.Journal of inherited metabolic disease · 2019Article
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Authors and funding
13 authors at 7 institutions in 6 countries.
Funding
Abstract
Homocystinuria is a rare inborn error of methionine metabolism caused by cystathionine β-synthase (CBS) deficiency. The prevalence of homocystinuria in Qatar is 1:1,800 births, mainly due to a founder Qatari missense mutation, c.1006C>T; p.R336C (p.Arg336Cys). We characterized the structure-function relationship of the p.R336C-mutant protein and investigated the effect of different chemical chaperones to restore p.R336C-CBS activity using three models: in silico, ΔCBS yeast, and CRISPR/Cas9 p.R336C knock-in HEK293T and HepG2 cell lines. Protein modeling suggested that the p.R336C induces severe conformational and structural changes, perhaps influencing CBS activity. Wild-type CBS, but not the p.R336C mutant, was able to restore the yeast growth in ΔCBS-deficient yeast in a complementation assay. The p.R336C knock-in HEK293T and HepG2 cells decreased the level of CBS expression and reduced its structural stability; however, treatment of the p.R336C knock-in HEK293T cells with betaine, a chemical chaperone, restored the stability and tetrameric conformation of CBS, but not its activity. Collectively, these results indicate that the p.R336C mutation has a deleterious effect on CBS structure, stability, and activity, and using the chemical chaperones approach for treatment could be ineffective in restoring p.R336C CBS activity.
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