title: Abnormal Hypermethylation at Imprinting Control Regions in Patients with S-Adenosylhomocysteine Hydrolase (AHCY) Deficiency.
abstract: S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare autosomal recessive disorder in methionine metabolism caused by mutations in the AHCY gene. Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, mostly associated with hypermethioninaemia, elevated serum creatine kinase levels and increased genome wide DNA methylation. The prime function of AHCY is to hydrolyse and efficiently remove S-adenosylhomocysteine, the by-product of transmethylation reactions and one of the most potent methyltransferase inhibitors. In this study, we set out to more specifically characterize DNA methylation changes in blood samples from patients with AHCY deficiency. Global DNA methylation was increased in two of three analysed patients. In addition, we analysed the DNA methylation levels at differentially methylated regions (DMRs) of six imprinted genes (MEST, SNRPN, LIT1, H19, GTL2 and PEG3) as well as Alu and LINE1 repetitive elements in seven patients. Three patients showed a hypermethylation in up to five imprinted gene DMRs. Abnormal methylation in Alu and LINE1 repetitive elements was not observed. We conclude that DNA hypermethylation seems to be a frequent but not a constant feature associated with AHCY deficiency that affects different genomic regions to different degrees. Thus AHCY deficiency may represent an ideal model disease for studying the molecular origins and biological consequences of DNA hypermethylation due to impaired cellular methylation status.
authors.affiliation: Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Motzek
authors.affiliation: Institute Ruđer Bošković, Division of Molecular Medicine, Zagreb, Croatia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Knežević
authors.affiliation: Institute for Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Switzeny
authors.affiliation: Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Alexis
authors.initials: A
authors.lastname: Cooper
authors.affiliation: Department of Pediatrics, University Hospital Center Zagreb & University of Zagreb, School of Medicine, Zagreb, Croatia.
authors.forename: Ivo
authors.initials: I
authors.lastname: Barić
authors.affiliation: Institute Ruđer Bošković, Division of Molecular Medicine, Zagreb, Croatia.
authors.forename: Robert
authors.initials: R
authors.lastname: Beluzić
authors.affiliation: Clinic for Special Children, Strasburg, Pennsylvania, United States of America.|Franklin and Marshall College, Lancaster, Pennsylvania, United States of America.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Strauss
authors.affiliation: Clinic for Special Children, Strasburg, Pennsylvania, United States of America.|Franklin and Marshall College, Lancaster, Pennsylvania, United States of America.
authors.forename: Erik G
authors.initials: EG
authors.lastname: Puffenberger
authors.affiliation: Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, Maryland, United States of America.
authors.forename: S Harvey
authors.initials: SH
authors.lastname: Mudd
authors.affiliation: Institute Ruđer Bošković, Division of Molecular Medicine, Zagreb, Croatia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Vugrek
authors.affiliation: Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zechner
mesh_terms: D020087:Alu Elements; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000235:genetics*; D003401:Creatine / Q000097:blood; D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting; D050938:Glycine N-Methyltransferase / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D020084:Long Interspersed Nucleotide Elements; D008297:Male
chemical_list: D050938:Glycine N-Methyltransferase; D003401:Creatine