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AuthorGupta, Sapna
AuthorGallego-Villar, Lorena
AuthorWang, Liqun
AuthorLee, Hyung-Ok
AuthorNasrallah, Gheyath
AuthorAl-Dewik, Nader
AuthorHäberle, Johannes
AuthorThöny, Beat
AuthorBlom, Henk J
AuthorBen-Omran, Tawfeg
AuthorKruger, Warren D
Available date2019-07-02T11:05:37Z
Publication Date2019-06-26
Publication NameJournal of Inherited Metabolic Disease
Identifierhttp://dx.doi.org/10.1002/jimd.12140
CitationGupta, S. , Gallego‐Villar, L. , Wang, L. , Lee, H. , Nasrallah, G. , Al‐Dewik, N. , Häberle, J. , Thöny, B. , Blom, H. J., Ben‐Omran, T. and Kruger, W. D. (2019), Analysis of the Qatari R336C Cystathionine β‐Synthase Protein in Mice. J Inherit Metab Dis. Accepted Author Manuscript. doi:10.1002/jimd.12140
ISSN0141-8955
URIhttp://hdl.handle.net/10576/11643
AbstractClassical homocystinuria is a recessive inborn error of metabolism caused by mutations in the cystathionine beta-synthase (CBS) gene. The highest incidence of CBS deficiency in the world is found in the country of Qatar due to the combination of high rates of consanguinity and the presence of a founder mutation, c.1006C>T (p.R336C). This mutation does not respond to pyridoxine and is considered severe. Here we describe the creation of a mouse that is null for the mouse Cbs gene and expresses human p.R336C CBS from a zinc-inducible transgene (Tg-R336C Cbs ). Zinc treated Tg-R336C Cbs mice have extreme elevation in both serum tHcy and liver tHcy compared to control transgenic mice. Both the steady-state protein levels and CBS enzyme activity levels in liver lysates from Tg-R336C Cbs mice are significantly reduced compared to that found in Tg-hCBS Cbs mice expressing wild-type human CBS. Treatment of Tg-R336C Cbs mice with the proteasome inhibitor bortezomib results in stabilization of liver CBS protein and an increase in activity to levels found in corresponding Tg-hCBS Cbs wild type mice. Surprisingly, serum tHcy did not fully correct even though liver enzyme activity was as high as control animals. This discrepancy is explained by in vitro enzymatic studies of mouse liver extracts showing that p.R336C causes reduced binding affinity for the substrate serine by almost seven-fold and significantly increased dependence on pyridoxal phosphate in the reaction buffer. These studies demonstrate that the p.R336C alteration effects both protein stability and substrate/cofactor binding.
SponsorNational Institute of Diabetes and Digestive and Kidney Diseases, Grant/Award Number: DK101404; Qatar Foundation, Grant/Award Number: NPR7‐355‐3‐088; NPRP grant, Grant/Award Number: NPR7‐355‐3‐088; National Institutes of Health, Grant/Award Numbers: P30 CA006927, R01 DK101404
Languageen
PublisherWiley
Subjecthomocysteine
inborn error
metabolism
methionine
missense mutation
mouse model
TitleAnalysis of the Qatari R336C Cystathionine β-Synthase Protein in Mice.
TypeArticle
ESSN1573-2665
dc.accessType Abstract Only


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