Methylation is an essential process in the body. Methyl groups in the form of S-adenosylmethionine are used for the synthesis of many essential compounds (e.g., creatine, phosphatidylcholine, and the methylation of DNA in gene expression). Glycine N-methyltransferase (GNMT) is an abundant enzyme in liver. It catalyzes the methylation of glycine by using S-adenosylmethionine (AdoMet) to form N-methylglycine (sarcosine) with the concommitant production of S-adenosylhomocysteine (AdoHcy). It plays an important role in the economy of methyl groups in the body. The function of GNMT has been hypothesized to provide an alternative route for the conversion of excess AdoMet to AdoHcy in order to preserve the AdoMet/AdoHcy ratio. GNMT is also inhibited by a specific form of folate, 5-methyltetrahydrofolate pentaglutamate. As such, GNMT participates in a regulatory scheme that links the de novo synthesis of methyl groups to the availability of dietary methionine. This hypothesis can now be tested in man. We report here for the first time two Italian sibs who are compound heterozygotes in the gene that encodes GNMT. Both have evidence of mild liver disease. Each bears the same two missense mutations, one in exon 1 (Leu49Pro) and the second in exon 4 (His176Asn). Restriction enzyme analysis of panels of diverse DNA samples indicates that these mutations are not attributable to a common polymorphism.
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