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AuthorIsmail, Hesham M
AuthorKrishnamoorthy, Navaneethakrishnan
AuthorAl-Dewik, Nader
AuthorZayed, Hatem
AuthorMohamed, Nura A
AuthorGiacomo, Valeria Di
AuthorGupta, Sapna
AuthorHäberle, Johannes
AuthorThöny, Beat
AuthorBlom, Henk J
AuthorKruger, Waren D
AuthorBen-Omran, Tawfeg
AuthorNasrallah, Gheyath K
Available date2018-11-14T11:38:12Z
Publication Date2018-11-01
Publication NameHuman Mutationen_US
Identifierhttp://dx.doi.org/10.1002/humu.23682
CitationIsmail, H. M., Krishnamoorthy, N. , Al‐Dewik, N. , Zayed, H. , Mohamed, N. A., Giacomo, V. D., Gupta, S. , Häberle, J. , Thöny, B. , Blom, H. J., Kruger, W. D., Ben‐Omran, T. and Nasrallah, G. K. (2018), In silico and in vivo models for Qatari‐Specific classical homocystinuria as basis for development of novel therapies. Human Mutation. Accepted Author Manuscript. . doi:10.1002/humu.23682
ISSN1059-7794
URIhttp://hdl.handle.net/10576/11180
AbstractHomocystinuria 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. Wildtype 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 reduce 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. This article is protected by copyright. All rights reserved.
SponsorQNRF
Languageen
PublisherWiley
SubjectCBS
SubjectHomocystinuria
SubjectQatar
Subjectchemical chaperones
Subjectin silico
Subjectin vivo models
Subjectp.R336C mutation
TitleIn silico and in vivo models for Qatari-Specific classical homocystinuria as basis for development of novel therapies.
TypeArticle
dc.identifier.essn 1098-1004


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