Skip to main content

Advertisement

SpringerLink
Log in

The Production of Transgenic Mice Expressing Human Cystathionine Beta-Synthase to Study Down Syndrome

  • Published:
Behavior Genetics Aims and scope Submit manuscript

 

Down syndrome (DS) is the most common genetic cause of significant cognitive disability. We hypothesize that by identifying metabolic alterations associated with cognitive impairment, it may be possible to develop medical or dietary interventions to ameliorate cognitive disabilities in persons with DS. Evidence suggests that one-carbon/transsulfuration (1C-TS) metabolism is abnormal in persons with DS. Cystathionine beta-synthase (CBS) plays a critical role in this metabolic system. The gene for CBS is on human chromosome 21, and there is evidence of elevated CBS enzyme activity in tissues and cells from individuals with DS. To analyze the possible role of CBS in Down syndrome, we have produced several lines of transgenic mice expressing the human CBS gene. We describe the use of Florescence Situ Hybridization (FISH) analysis to characterize the transgene insertion site for each line. Our initial expression analysis of each transgenic line by RT-PCR shows that the tissue specificity of human CBS mRNA levels in these mice may differ from the tissue specificity of mouse CBS mRNA levels in the same animals. These mice will be invaluable for assessing the regulation of the CBS gene and the role of CBS in cognition. They can also be used to develop therapies that target abnormalities in 1C-TS metabolism to improve cognition in persons with DS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.

Similar content being viewed by others

References

  • Al-Gazali L. I., Padmanabhan R., Melnyk S., Yi P., Pogribny I. P., Pogribna M., Bakir M., Hamid Z. A., Abdulrazzaq Y., Dawodu A. and James S. J. (2001) Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neural tube defect. Am. J. Med. Genet. 103:128–132

    Article  PubMed  CAS  Google Scholar 

  • Altschul S. F., Gish W., Miller W., Myers E. W. and Lipman D. J. (1990). Basic local alignment search tool. J. Mol. Biol. 215:403–410

    Article  PubMed  CAS  Google Scholar 

  • Bao L., Vlcek C., Paces V. and Kraus J. P. (1998) Identification and tissue distribution of human cystathionine beta synthase mRNA isoforms. Arch. Biochem. Biophys. 350:95–103

    Article  PubMed  CAS  Google Scholar 

  • Chadefaux B., Rethore M. O., Raoul O., Ceballos I., Poissonnier M., Gilgenkranz S. and Allard D. (1985) Cystathionine beta synthase: gene dosage effect in trisomy 21. Biochem. Biophys. Res. Comm. 128:40–44

    Article  PubMed  CAS  Google Scholar 

  • Costa A. C. and Patterson D. (2005). Down syndrome and genetics – a case of linked histories. Nat. Rev Genet. 6:137–147

    Article  PubMed  Google Scholar 

  • Davisson M. T., Schmidt C., Reeves R. H., Irving N. G., Akeson E. C., Harris B. S. and Bronson R. T. (1993). Segmental trisomy as a mouse model for Down syndrome. Prog. Clin. Biol. Res. 384:117–133

    PubMed  CAS  Google Scholar 

  • Deutsch S., Lyle R., Dermitzakis E. T., Attar H. Subrahmanyan L., Gehrig C., Parand L., Gagnebin M., Rougemont J., Jongeneel C. V. and Antonarakis S. E. (2005). Gene expression variation and expression quantitative trait mapping of human chromosome 21 genes. Hum. Mol. Genet. 14:3741–3749

    Article  PubMed  CAS  Google Scholar 

  • Eto K. and Kimura H. (2002) A novel enhancing mechanism for hydrogen sulfide-producing activity of cystathionine beta-synthase. J. Biol. Chem. 277:42680–42685

    Article  PubMed  CAS  Google Scholar 

  • Ge Y., Jensen T. L., Matherly L. H. and Taub J. W. (2002). Synergistic regulation of human cystathionine beta-synthase −1b promoter by transcription factors NF-YA isoforms and Sp1. Biochimica et Biophysica Acta 1579:73–80

    PubMed  CAS  Google Scholar 

  • Granholm A.-C., Ford K. A., Hyde L. A., Bimonte H. A., Hunter C. L., Nelson M., Albeck D., Sanders L. A., Mufson E. J. and Crnic L. S. (2002) Estrogen restores cognition and cholinergic phenotype in an animal model of Down syndrome. Physiol. Behav. 77:371–385

    Article  PubMed  CAS  Google Scholar 

  • Gueant J.-L, Anello G., Bosco P., Gueant-Rodriquez R., Romano A., Barone C., Gerard P. and Romano C. (2005). Homocysteine and related genetic polymorphisms in Down’s syndrome IQ. J. Neurol. Neurosurg. Psychiatry. 76:706–709

    Article  PubMed  Google Scholar 

  • Hattori, M., Fujiyama, A., Taylor, T. D., Watanabe, H., Yada, T., Park, H. S., Toyoda, A., Ishii, K., Totoki, Y., Choi, D. K., Groner, Y., Soeda, E., Ohki, M., Takagi, T., Sakaki, Y., Taudien, S., Blechschmidt, K., Polley, A., Menzel, U., Delabar, J., Kumpf, K., Lehmann, R., Patterson, D., Reichwald, K., Rump, A., Schillhabel, M., Schudy, A., Zimmermann, W., Rosenthal, A., Kudoh, J., Schibuya, K., Kawasaki, K., Asakawa, S., Shintani, A., Sasaki, T., Nagamine, G., Hornischer, K., Brant, P., Scharfe, M., Schon, O., Desario, A., Reichelt, J., Kauer, G., Blocker, H., Ramser, J., Beck, A., Klages, S., Hennig, S., Riesselmann, L., Dagand, E., Haaf, T., Wehrmeyer, S., Borzym, K, Gardiner, K., Nizetic, D., Francis, F., Lehrach, H., Reinhardt. R., Yaspo, M.-L., and Chromosome 21 Mapping and Sequencing Consortium. (2000). The DNA sequence of human chromosome 21. Nature 405:311–319

    Article  PubMed  CAS  ADS  Google Scholar 

  • Hogan B., Beddington R., Costantini F., and Lacy E. (1994) Manipulating the Mouse Embryo: A Laboratory Manual. Cold Spring Harbor Press, New York

    Google Scholar 

  • Ichinohe A., Kanaume T., Takashima S., Enokido Y., Nagai Y., Kimura H. (2005). Cystathionine beta synthase is enriched in the brains of Down’s patients. Biochem. Biophys. Res. Comm. 338:1547–1550

    Article  PubMed  CAS  Google Scholar 

  • Induced Mutant Resources: Tail DNA for PCR (No Organic Solvents). The Jackson Laboratory. 2005. http://www.jax.org/imr/tail_nonorg.html

  • Kamoun P. (2001) Mental retardation in Down syndrome: a hydrogen sulfide hypothesis. Med. Hypotheses 57:389–392

    Article  PubMed  CAS  Google Scholar 

  • Kamoun P., Belardinelli M. C., Chabli A., Lallouchi K. and Chadefaux-Vekemans B. (2003) Endogenous hydrogen sulfide overproduction in Down syndrome. Am. J. Med. Genet. 116A:310–311

    Article  Google Scholar 

  • Korenberg J. R., Chen X. N., Devon K. L., Noya D., Oster-Granite M. L. and Birren B.W (1999). Mouse molecular cytogenetic resource: 157 BACs link the chromosomal and genetic maps. Genome Res. 9:514–523

    Article  PubMed  CAS  Google Scholar 

  • Kraus J. P., Oliveriusova J., Sokolova J., Kraus E., Vicek C., De Franchis R., MacLean K. N., Bao L., Bukoskova G., Patterson D., Paces V., Ansorge W. and Kozich V. (1998). The human cystathionine beta-synthase (CBS) gene: complete sequence, alternative splicing, and polymorphisms. Genomics 52:312–324

    Article  PubMed  CAS  Google Scholar 

  • Lejeune J. (1990). Pathogenesis of mental deficiency in trisomy 21. Am. J. Med. Genet. Supp. 7:20–30

    Article  CAS  Google Scholar 

  • Lejeune J., Rethore M. O., de Blois M. C., Maunoury-Burolla C., Mir M., Nicolle L., Borowy F., Borghi E. and Recan D. (1986). Metabolism of monocarbons and trisomy 21: sensitivity to methotrexate. Ann. Genet. 29:16–19

    PubMed  CAS  Google Scholar 

  • Liu M., Ge Y., Cabelof D. C., Aboukamel A., Heydari A. R., Mohammad R. and Matherly L. H. (2005). Structure and regulation of four noncoding exons and promoters and regulation by dietary folates. J. Biol. Chem. 280:5588–5597

    Article  PubMed  CAS  Google Scholar 

  • MacLean K. N., Kraus E. and Kraus J. P. (2004). The dominant role of Sp1 in regulating the cystathionine beta synthase −1a and −1b promoters facilitates potential tissue-specific regulation by Kruppel-like factors. J. Biol. Chem. 279:8558–8566

    Article  PubMed  CAS  Google Scholar 

  • Metaphase Preparation from Mouse/Rat Spleen, Section of Cancer Genomics, Genetics Branch, NCI National Institutes of Health, 2005 http://www.riedlab.nci.nih.gov/publications/MetPrep_SpleenRatMouse.pdf

  • Miles E. W. and Kraus J. P. (2004). Cystathionine beta synthase: structure, function, regulation, and location of homocystinuria-causing mutations. J. Biol. Chem. 279:29871–29874

    Article  PubMed  CAS  Google Scholar 

  • Mudd, S. H., Levy, H. L., and Kraus, J. P. (2001). In C. R. Scriver, A. L. Beaudet, D. Valle, W. S. Sly, D. Chiles, K.W. Kinsler, and B. Vogelstein (eds.), The Metabolic and Molecular Bases of Inherited Disease (8th edn.), Vol. 2, McGraw-Hill, Inc., New York, pp. 2007–2056

  • Munke M., Kraus J. P., Ohura T. and Francke U. (1988). The gene for cystathionine beta-synthase (CBS) maps to the subtelomeric region on human chromosome 21q and to proximal mouse chromosome 17. Am. J. Hum. Genet. 42:550–550

    PubMed  CAS  Google Scholar 

  • Pacheco T. R., Gomes A. Q., Barbosa-Morais N. L., Benes V., Ansorge W., Wollerton M., Smith C. W., Valcarcel J. and Carmo-Fonseca M. (2004). Diversity of vertebrate splicing factor U2AF35. J. Biol. Chem. 279:27039–27049

    Article  PubMed  CAS  Google Scholar 

  • Peeters M. A., Poon A., Zipursky A., and Lejeune J. (1986).Toxicity of leukaemia therapy in children with Down syndrome. Lancet, 1279, November 29, 1986

    Google Scholar 

  • Peeters M. A., Rethore M. O. and Lejeune J. (1995). In vivo folic acid supplementation partially corrects in vitro methotrexate toxicity in patients with Down syndrome. Br. J. Haematol. 89:678–680

    PubMed  CAS  Google Scholar 

  • Pogribna M., Melnyk S., Pogribny I., Chango A., Yi P. and James S. J. (2001). Homocysteine metabolism in children with Down syndrome: in vitro modulation. Am J Hum Genet 69:88–95

    Article  PubMed  CAS  Google Scholar 

  • Quere I., Paul V., Roulliac C., Janbon C., London J., Demaille J., Kamoun P., Difier J. L., Abitol M. and Chasse J. F. (1999). Spatial and temporal expression of the cystathionine beta synthase gene during early human development. Biochem. Biophys. Res. Comm. 254:127–137

    Article  PubMed  CAS  Google Scholar 

  • Robert K., Vialard F., Thiery E., Toyama K., Sinet P.-M., Janel N. and London J. (2003). Expression of the cystathionine beta synthase gene during mouse development and immunolocalization in the adult brain. J. Histochem. Cytochem. 51:363–371

    PubMed  CAS  Google Scholar 

  • Roizen N. J. and Patterson D. (2003). Down’s syndrome. Lancet, 361:1281–1289

    Article  PubMed  Google Scholar 

  • Rozen S. and Skaletsky H. J. (2000). Primer3 on the WWW for general users and for biologist programmers. In: Krawetz S., Misener S. (eds), Bioinformatics Methods and Protocols: Methods in Molecular Biology. Humana Press, Totowa NJ, pp 365–386

    Google Scholar 

  • Salman M. (2002). Systematic review of the effects of therapeutic dietary supplements and drugs on cognitive function in subjects with Down syndrome. Eur. J. Paediatr. Neurol. 6:213–219

    Article  PubMed  Google Scholar 

  • Sax C. M., Cvekl A. and Piatigorsky J. (1997). Transcriptional regulation of mouse alpha A-crystallin gene: binding of USF to the −7/+5 region. Genes 185:209–216

    Article  CAS  Google Scholar 

  • Wang L., Jhee K.-H., Hua X., DiBello P. M., Jacobsen D. W. and Kruger W. D. (2004). Modulation of cystathionine beta-synthase level regulates total serum homocysteine in mice. Circ. Res. 94:1318–1324

    Article  PubMed  CAS  Google Scholar 

  • Watanabe M., Osada J., Aratani Y., Kluckman K., Reddick R., Malinow M. R. and Maeda N. (1995). Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia. Proc. Natl. Acad. Sci. USA 92:1585–1589

    Article  PubMed  CAS  ADS  Google Scholar 

  • Whetstine J. R., Flatley R. M. and Matherly L. H. (2002). The human reduced folate carrier gene is ubiquitously and differentially expressed in normal human tissues: identification of seven non-coding exons and characterization of a novel promoter. Biochem. J. 367:629–640

    Article  PubMed  CAS  Google Scholar 

  • Zou C. G. and Banerjee R. (2003). Tumor necrosis factor-alpha-induced targeted proteolysis of cystathionine beta-synthase modulates redox homeostasis. J. Biol. Chem. 278:16802–16808

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was funded by a grant from the Fondation Jerome Lejeune (DP) and a grant from the National Institute of Child Health and Human Development (NICHD) (DP). The authors thank Drs. Jan Kraus and Jana Oliveriusova (University of Colorado at Denver and Health Sciences Center) for assistance in DNA preparation for FISH and Jean Smith and Lynne Meltesen (Colorado Genetics Laboratory, Department of Pathology, University of Colorado at Denver and Health Sciences Center) for the FISH analysis. This manuscript is dedicated to the memory of Dr. Linda Crnic, a dear and valued colleague and friend.

Author information

Authors and Affiliations

  1. The Eleanor Roosevelt Institute at the University of Denver, 1899 Gaylord St., Denver, CO, 80206, USA

    Christine Butler, Aaron J. Knox, Jeffrey Bowersox, Stacy Forbes & David Patterson

  2. Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA

    Aaron J. Knox & David Patterson

  3. The Eleanor Roosevelt Institute and the Department of Biological Sciences, The University of Denver, 1899 Gaylord St., Denver, CO, 80206, USA

    David Patterson

Authors
  1. Christine Butler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aaron J. Knox
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeffrey Bowersox
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stacy Forbes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Patterson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Patterson.

Additional information

Edited by Pierre L. Roubertoux

Rights and permissions

Reprints and permissions

About this article

Cite this article

Butler, C., Knox, A.J., Bowersox, J. et al. The Production of Transgenic Mice Expressing Human Cystathionine Beta-Synthase to Study Down Syndrome. Behav Genet 36, 429–438 (2006). https://doi.org/10.1007/s10519-006-9046-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10519-006-9046-y

KEY WORDS:

Search

Navigation