Mouse modeling and structural analysis of the p.G307S mutation in human cystathionine β-synthase (CBS ) reveal effects on CBS activity but not stability

The Journal of Biological Chemistry
Sapna GuptaWarren D Kruger

Abstract

Mutations in the cystathionine β-synthase (CBS) gene are the cause of classical homocystinuria, the most common inborn error in sulfur metabolism. The p.G307S mutation is the most frequent cause of CBS deficiency in Ireland, which has the highest prevalence of CBS deficiency in Europe. Individuals homozygous for this mutation tend to be severely affected and are pyridoxine nonresponsive, but the molecular basis for the strong effects of this mutation is unclear. Here, we characterized a transgenic mouse model lacking endogenous Cbs and expressing human p.G307S CBS protein from a zinc-inducible metallothionein promoter (Tg-G307S Cbs-/-). Unlike mice expressing other mutant CBS alleles, the Tg-G307S transgene could not efficiently rescue neonatal lethality of Cbs-/- in a C57BL/6J background. In a C3H/HeJ background, zinc-induced Tg-G307S Cbs-/- mice expressed high levels of p.G307S CBS in the liver, and this protein variant forms multimers, similarly to mice expressing WT human CBS. However, the p.G307S enzyme had no detectable residual activity. Moreover, treating mice with proteasome inhibitors failed to significantly increase CBS-specific activity. These findings indicated that the G307S substitution likely affects catalytic f...Continue Reading

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Citations

Mar 21, 2019·Frontiers in Molecular Biosciences·Jing LiangJianyong Li
Apr 5, 2020·Genes·Duaa W Al-Sadeq, Gheyath K Nasrallah
May 6, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sapna GuptaWarren D Kruger
Sep 9, 2021·Journal of Biomolecular Structure & Dynamics·Aashish Bhatt, Md Ehesan Ali

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