title: Glycine N-methyltransferase-/- mice develop chronic hepatitis and glycogen storage disease in the liver.
abstract: Glycine N-methyltransferase (GNMT) affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens. To establish a Gnmt knockout mouse model, 2 lambda phage clones containing a mouse Gnmt genome were isolated. At 11 weeks of age, the Gnmt-/- mice had hepatomegaly, hypermethioninemia, and significantly higher levels of both serum alanine aminotransferase and hepatic S-adenosylmethionine. Such phenotypes mimic patients with congenital GNMT deficiencies. A real-time polymerase chain reaction analysis of 10 genes in the one-carbon metabolism pathway revealed that 5,10-methylenetetrahydrofolate reductase, S-adenosylhomocysteine hydrolase (Ahcy), and formiminotransferase cyclodeaminase (Ftcd) were significantly down-regulated in Gnmt-/- mice. This report demonstrates that GNMT regulates the expression of both Ftcd and Ahcy genes. Results from pathological examinations indicated that 57.1% (8 of 14) of the Gnmt-/- mice had glycogen storage disease (GSD) in their livers. Focal necrosis was observed in male Gnmt-/- livers, whereas degenerative changes were found in the intermediate zones of female Gnmt-/- livers. In addition, hypoglycemia, increased serum cholesterol, and significantly lower numbers of white blood cells, neutrophils, and monocytes were observed in the Gnmt-/- mice. A real-time polymerase chain reaction analysis of genes involved in the gluconeogenesis pathways revealed that the following genes were significantly down-regulated in Gnmt-/- mice: fructose 1,6-bisphosphatase, phosphoenolpyruvate carboxykinase, and glucose-6-phosphate transporter.
  
  
  CONCLUSIONS
  Because Gnmt-/- mice phenotypes mimic those of patients with GNMT deficiencies and share several characteristics with GSD Ib patients, we suggest that they are useful for studies of the pathogenesis of congenital GNMT deficiencies and the role of GNMT in GSD and liver tumorigenesis.
authors.affiliation: Division of Preventive Medicine, Institute of Public Health, School of Medicine, Taipei, Taiwan.
authors.forename: Shih-Ping
authors.initials: SP
authors.lastname: Liu
authors.forename: Ying-Shiuan
authors.initials: YS
authors.lastname: Li
authors.forename: Yann-Jang
authors.initials: YJ
authors.lastname: Chen
authors.forename: En-Pei
authors.initials: EP
authors.lastname: Chiang
authors.forename: Anna Fen-Yau
authors.initials: AF
authors.lastname: Li
authors.forename: Ying-Hue
authors.initials: YH
authors.lastname: Lee
authors.forename: Ting-Fen
authors.initials: TF
authors.lastname: Tsai
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.forename: Shiu-Feng
authors.initials: SF
authors.lastname: Huang
authors.forename: Shiu-Feng
authors.initials: SF
authors.lastname: Hwang
authors.forename: Yi-Ming Arthur
authors.initials: YM
authors.lastname: Chen
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D050938:Glycine N-Methyltransferase / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism*; D006008:Glycogen Storage Disease / Q000378:metabolism*; D006521:Hepatitis, Chronic / Q000378:metabolism*; D006710:Homocysteine / Q000097:blood; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008715:Methionine / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism
chemical_list: D011506:Proteins; D006710:Homocysteine; D012436:S-Adenosylmethionine; D006003:Glycogen; D012435:S-Adenosylhomocysteine; D008715:Methionine; D050938:Glycine N-Methyltransferase; D000410:Alanine Transaminase; D000074183:ATPases Associated with Diverse Cellular Activities; C525034:Pex6 protein, mouse