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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
- Source :
- Molecular Genetics and Metabolism
- Publication Year :
- 2010
- Publisher :
- Elsevier BV, 2010.
-
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 6 months. Tail bleeding determinations indicate that HO mice are in a hypercoagulative state that is significantly ameliorated by betaine treatment in a manner that recapitulates the disease as it occurs in humans. Our findings indicate that this mouse model will be a valuable tool in the study of pathogenesis in classical homocystinuria and the rational design of novel treatments.
- Subjects :
- AdoHcy, S-adenosylhomocysteine
CBS, cystathionine beta-synthase
Homocysteine
AdoMet, S-adenosylmethionine
Endocrinology, Diabetes and Metabolism
Betaine—homocysteine S-methyltransferase
Biochemistry
Mice
chemistry.chemical_compound
0302 clinical medicine
Endocrinology
Fibrosis
0303 health sciences
biology
Cystathionine gamma-lyase
Blood Coagulation Disorders
3. Good health
Homocystinuria
MTHFR, methylenetetrahydrofolate reductase
Genetically modified mouse
medicine.medical_specialty
Cystathionine beta-Synthase
tHcy, total homocysteine
Mice, Transgenic
Article
03 medical and health sciences
Cystathionine
Internal medicine
medicine
Genetics
BHMT, betaine-homocysteine S-methyltransferase
Animals
HCU, classical homocystinuria
Molecular Biology
030304 developmental biology
Coagulation
Hcy, homocysteine
medicine.disease
Cystathionine beta synthase
Betaine
Fatty Liver
Disease Models, Animal
chemistry
CGL, cystathionine gamma-lyase
biology.protein
Steatosis
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 10967192
- Volume :
- 101
- Issue :
- 2-3
- Database :
- OpenAIRE
- Journal :
- Molecular Genetics and Metabolism
- Accession number :
- edsair.doi.dedup.....dfa311a214521f5b818ba15f40c7edef
- Full Text :
- https://doi.org/10.1016/j.ymgme.2010.06.010