Argininosuccinate synthetase gene is silenced by CpG methylation in children with phenylketonuria |
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Authors: | Li Li ChunMei Jin LiTao Ye GenZe Shao LiDe Wang Ming Lin |
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Affiliation: | 1. Department of Cell Biology, School of Basic Medical Sciences, Peking University, Beijing 100191, China;2. Yinchuan Maternal and Child Health Hospital, Yinchuan 750001, China;3. The National Key Facility for Crop Gene Resources and Genetic Improvement, Chinese Academy of Agricultural Sciences, Beijing 100081, China;4. Health Science Center, Peking University, Beijing 100191, China |
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Abstract: | ObjectivesThe concentration of tyrosine and the ratio of branch-amino acid to the aromatic amino acid in phenylketonuria (PKU) patients are much lower than that of normal people, which reveal that PKU patients have amino acid metabolism disorder. The aim of the present study was to investigate the arginine level in blood, the expression of argininosuccinate synthetase (ASS), the rate-limiting enzyme in arginine synthesis pathway, and the methylation of ASS in patients with PKU.Design and MethodsTwenty-five children with PKU and 65 healthy controls were investigated in this study. Blood concentration of arginine was analyzed by automatic amino acid analyzer. The methylation of ASS gene promoter was evaluated by using methylation-specific polymerase chain reaction (MSP) and bisulfite sequencing PCR (BSP) methods, and the mRNA level of ASS was evaluated by semi-quantitative RT-PCR.ResultsBlood concentration of arginine in PKU patients without dietary control was 0.017 ± 0.009 mmol/L while in normal persons was 0.129 ± 0.007 mmol/L, which is statistically significant (P < 0.001). The promoter of ASS was methylated in PKU (15/15, 100%) but not in normal persons (0/15). The mRNA level of ASS in PKU patients was lower than that of normal people, which was well correlated with its methylation status.ConclusionsThe silencing of ASS due to aberrant promoter CpG methylation may be an important mechanism for arginine biosynthesis disorders in PKU. High levels of phenylalanine and low levels of arginine are common characteristics in PKU patients. These findings would extend the current understanding of arginine, ASS in the development of PKU disease. |
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Keywords: | ASS gene Phenylketonuria Methylation Arginine |
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