A novel transgenic mouse model of CBS-deficient homocystinuria does not incur hepatic steatosis or fibrosis and exhibits a hypercoagulative phenotype that is ameliorated by betaine treatment.

Molecular Genetics and Metabolism
Kenneth N MacleanJan P Kraus

Abstract

Cystathionine beta-synthase (CBS) catalyzes the condensation of homocysteine (Hcy) and serine to cystathionine, which is then hydrolyzed to cysteine by cystathionine gamma-lyase. Inactivation of CBS results in CBS-deficient homocystinuria more commonly referred to as classical homocystinuria, which, if untreated, results in mental retardation, thromboembolic complications, and a range of connective tissue disorders. The molecular mechanisms that underlie the pathology of this disease are poorly understood. We report here the generation of a new mouse model of classical homocystinuria in which the mouse cbs gene is inactivated and that exhibits low-level expression of the human CBS transgene under the control of the human CBS promoter. This mouse model, designated "human only" (HO), exhibits severe elevations in both plasma and tissue levels of Hcy, methionine, S-adenosylmethionine, and S-adenosylhomocysteine and a concomitant decrease in plasma and hepatic levels of cysteine. HO mice exhibit mild hepatopathy but, in contrast to previous models of classical homocystinuria, do not incur hepatic steatosis, fibrosis, or neonatal death with approximately 90% of HO mice living for at least 6months. Tail bleeding determinations indica...Continue Reading

References

Jun 5, 2007·Experimental and Molecular Pathology·Julien HameletNathalie Janel

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Citations

Sep 29, 2011·Molecular and Cellular Biochemistry·Aline A da CunhaAngela T S Wyse
Mar 31, 2012·Current Gerontology and Geriatrics Research·Guido N VacanoDavid Patterson
Oct 26, 2010·American Journal of Physiology. Heart and Circulatory Physiology·Richard S Beard, Shawn E Bearden
Aug 2, 2015·Journal of Inherited Metabolic Disease·Sapna GuptaWarren D Kruger
May 18, 2016·The Journal of Clinical Investigation·Erez M BublilJan P Kraus
Sep 7, 2017·Antioxidants & Redox Signaling·Tomas MajtanJan P Kraus
Aug 9, 2018·British Journal of Pharmacology·Joshua B KohlGuenter Schwarz
Mar 6, 2018·Frontiers in Cell and Developmental Biology·Shubhangi PrabhudesaiRamani Ramchandran
Dec 1, 2018·British Journal of Pharmacology·Julie J LoiselleLingyun Wu
Nov 6, 2013·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sapna GuptaWarren D Kruger
Jun 4, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Hua JiangKenneth N Maclean
Nov 5, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kenneth N MacleanJames R Roede
Aug 28, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Tomas MajtanJan P Kraus
Feb 16, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kenneth N MacleanSally P Stabler
Nov 16, 2016·Cellular and Molecular Life Sciences : CMLS·Peter RoseYi Zhun Zhu
Aug 21, 2020·Reproductive Sciences·Damian D GuerraK Joseph Hurt
May 6, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sapna GuptaWarren D Kruger
Jul 18, 2018·European Journal of Pharmacology·Paolo FagoneFerdinando Nicoletti

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Methods Mentioned

BETA
transgenic
PCR
genotyping
biopsies
PCRs
electron microscopy

Software Mentioned

Quantity One
Prophet

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