Motzek Antje, Knežević Jelena, Switzeny Olivier J, Cooper Alexis, Barić Ivo, Beluzić Robert, Strauss Kevin A, Puffenberger Erik G, Mudd S Harvey, Vugrek Oliver, Zechner Ulrich
Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Institute Ruđer Bošković, Division of Molecular Medicine, Zagreb, Croatia.
PLoS One. 2016 Mar 14;11(3):e0151261. doi: 10.1371/journal.pone.0151261. eCollection 2016.
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.
S-腺苷同型半胱氨酸水解酶（AHCY）缺乏症是一种罕见的常染色体隐性蛋氨酸代谢紊乱疾病，由AHCY基因突变引起。主要特征为出生时即出现精神运动发育迟缓，包括髓鞘形成延迟和肌病（肌张力减退、腱反射消失等），大多与高甲硫氨酸血症、血清肌酸激酶水平升高及全基因组DNA甲基化增加有关。AHCY的主要功能是水解并有效清除S-腺苷同型半胱氨酸，它是转甲基反应的副产物，也是最有效的甲基转移酶抑制剂之一。在本研究中，我们旨在更具体地描述AHCY缺乏症患者血液样本中的DNA甲基化变化。在三名接受分析的患者中，有两名患者的全基因组DNA甲基化增加。此外，我们分析了七名患者中六个印记基因（MEST、SNRPN、LIT1、H19、GTL2和PEG3）以及Alu和LINE1重复元件的差异甲基化区域（DMR）的DNA甲基化水平。三名患者在多达五个印记基因DMR中表现出高甲基化。未观察到Alu和LINE1重复元件的异常甲基化。我们得出结论，DNA高甲基化似乎是与AHCY缺乏症相关的常见但非恒定特征，它对不同基因组区域的影响程度不同。因此，AHCY缺乏症可能是研究由于细胞甲基化状态受损导致的DNA高甲基化的分子起源和生物学后果的理想模型疾病。
