title: Normal brain myelination in a patient homozygous for a mutation that encodes a severely truncated methionine adenosyltransferase I/III.
abstract: Two isozymes of mammalian methionine adenosyltransferase, MAT I and MAT III, are expressed solely in adult liver. They are, respectively, tetramers and dimers of a single subunit encoded by the gene MAT1A. A third isozyme, MAT II, contains a catalytic subunit encoded by a separate gene, MAT2A, and is expressed in a variety of tissues, including (to a slight extent) adult liver. Based on a recent finding that 2 children with isolated hypermethioninemia and brain demyelination were homozygous for MAT1A mutations predicted to produce severely truncated proteins, and devoid of activity when expressed, it was concluded that complete lack of MAT I/III activity may be associated with neurological symptoms and demyelination. We now report that a 43-year-old man with persistent isolated hypermethioninemia, previously demonstrated to have deficient MAT activity in his liver, has normal brain myelination on MRI and normal neurological function, despite being homozygous for a 539 TG insertion in exon V of MAT1A, so that the gene is predicted to encode a protein of only 184 rather than the normal 395 amino acids. This patient's exon V mutation was demonstrated by SSCP analysis and verified by sequencing. Both parents are heterozygous for the same insertion. This suggests that MAT1A mutations producing severely truncated proteins do not necessarily produce brain demyelination. This finding has relevance to a previously reported 4-year-old girl who was also homozygous for the 539insTG mutation. Finally, our patient's 7% residual hepatic MAT activity, measured at 1 mM methionine, may reflect the hepatic activity of the more ubiquitous enzyme form, MAT II.
authors.affiliation: Section on Human Biochemical Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland 20892-1830, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hazelwood
authors.forename: I
authors.initials: I
authors.lastname: Bernardini
authors.forename: V
authors.initials: V
authors.lastname: Shotelersuk
authors.forename: A
authors.initials: A
authors.lastname: Tangerman
authors.forename: J
authors.initials: J
authors.lastname: Guo
authors.forename: H
authors.initials: H
authors.lastname: Mudd
authors.forename: W A
authors.initials: WA
authors.lastname: Gahl
mesh_terms: D000328:Adult; D001921:Brain / Q000378:metabolism*; D001944:Breath Tests; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004220:Disulfides / Q000652:urine; D005260:Female; D006720:Homozygote; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D008715:Methionine / Q000378:metabolism; D008716:Methionine Adenosyltransferase / Q000172:deficiency* / Q000235:genetics; D009186:Myelin Sheath / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics; D013440:Sulfides / Q000032:analysis
chemical_list: D004220:Disulfides; D007527:Isoenzymes; D013440:Sulfides; D008715:Methionine; D008716:Methionine Adenosyltransferase; C004784:dimethyl sulfide