title: Adenosine-deaminase-deficient mice die perinatally and exhibit liver-cell degeneration, atelectasis and small intestinal cell death.
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.
authors.affiliation: Laboratory for Molecular Carcinogenesis, Sylvius Laboratories, Leiden University, The Netherlands.
authors.forename: A A
authors.initials: AA
authors.lastname: Migchielsen
authors.forename: M L
authors.initials: ML
authors.lastname: Breuer
authors.forename: M A
authors.initials: MA
authors.lastname: van Roon
authors.forename: H
authors.initials: H
authors.lastname: te Riele
authors.forename: C
authors.initials: C
authors.lastname: Zurcher
authors.forename: F
authors.initials: F
authors.lastname: Ossendorp
authors.forename: S
authors.initials: S
authors.lastname: Toutain
authors.forename: M S
authors.initials: MS
authors.lastname: Hershfield
authors.forename: A
authors.initials: A
authors.lastname: Berns
authors.forename: D
authors.initials: D
authors.lastname: Valerio
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D016923:Cell Death; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology; D005260:Female; D018390:Gene Targeting; D006720:Homozygote; D006801:Humans; D007421:Intestine, Small / Q000473:pathology*; D008099:Liver / Q000473:pathology*; D008297:Male; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011247:Pregnancy; D001261:Pulmonary Atelectasis / Q000235:genetics*; D011687:Purines / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000209:etiology; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D017931:DNA Primers; D011687:Purines; D000243:Adenosine Deaminase