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Adenosine–deaminase–deficient mice die perinatally and exhibit liver–cell degeneration, atelectasis and small intestinal cell death

Nature Genetics volume 10, pages 279–287 (1995)Cite this article

Abstract

We report the generation and characterization of mice lacking adenosine deaminase (ADA). In humans, absence of ADA causes severe combined immunodeficiency. In contrast, ADA–deficient mice die perinatally with marked liver–cell degeneration, but lack abnormalities in the thymus. The ADA substrates, adenosine and deoxyadenosine, are increased in ADA–deficient mice. Adenine deoxyribonucleotides are only modestly elevated, whereas S–adenosylhomocysteine hydrolase activity is reduced more than 85%. Consequently, the ratio of S–adenosylhomocysteine (AdoMet) to S–adenosyl homocysteine (AdoHcy) is reduced threefold in liver. We conclude that ADA plays a more critical role in murine than human fetal development. The murine liver pathology may be due to AdoHcy–mediated inhibition of AdoMet–dependent transmethylation reactions.

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Authors and Affiliations

  1. Gene Therapy Working Group, Laboratory for Molecular Carcinogenesis, Sylvius Laboratories, Leiden University, Wassenaarseweg 72, P.O. Box 9503, Leiden, 2300 RA, The Netherlands

    Alexandra A.J. Migchielsen, Marco L. Breuer & Dinko Valerio

  2. Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands

    Marian A. van Roon, Hein te Riele & Anton Berns

  3. TNO-Biomedical Primate Research Centre, Lange Kleiweg 151, 2280 HV, Rijswijk, The Netherlands

    Chris Zurcher

  4. Immunohematology and Bloodbank, Academical Hospital Leiden, The Netherlands

    Ferry Ossendorp

  5. Department of Rheumatology and Immunology, Duke University Medical Center, Durham, North Carolina, 27710, USA

    Stephan Toutain & Michael S. Hershfield

  6. IntroGene BV, Lange Kleiweg 151, 2280 GG, Rÿswijk, The Netherlands

    Dinko Valerio

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Migchielsen, A., Breuer, M., van Roon, M. et al. Adenosine–deaminase–deficient mice die perinatally and exhibit liver–cell degeneration, atelectasis and small intestinal cell death. Nat Genet 10, 279–287 (1995). https://doi.org/10.1038/ng0795-279

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