RGD Reference Report - Dominant inheritance of isolated hypermethioninemia is associated with a mutation in the human methionine adenosyltransferase 1A gene. - Rat Genome Database

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Dominant inheritance of isolated hypermethioninemia is associated with a mutation in the human methionine adenosyltransferase 1A gene.

Authors: Chamberlin, ME  Ubagai, T  Mudd, SH  Levy, HL  Chou, JY 
Citation: Chamberlin ME, etal., Am J Hum Genet. 1997 Mar;60(3):540-6.
RGD ID: 1599915
Pubmed: PMID:9042912   (View Abstract at PubMed)
PMCID: PMC1712529   (View Article at PubMed Central)

Methionine adenosyltransferase (MAT) I/III deficiency, characterized by isolated persistent hypermethioninemia, is caused by mutations in the MAT1A gene encoding MAT(alpha)1, the subunit of major hepatic enzymes MAT I ([alpha1]4) and III([alpha1]2). We have characterized 10 MAT1A mutations in MAT I/III-deficient individuals and shown that the associated hypermethioninemic phenotype was inherited as an autosomal recessive trait. However, dominant inheritance of hypermethioninemia, also hypothesized to be caused by MAT I/III deficiency, has been reported in two families. Here we show that the only mutation uncovered in one of these families, G, is a G-->A transition at nt 791 in exon VII of one MAT1A allele that converts an arginine at position 264 to a histidine (R264H). This single allelic R264H mutation was subsequently identified in two hypermethioninemic individuals in an additional family, C. Family C members were also found to inherit hypermethioninemia in a dominant fashion, and the available affected members analyzed carried the single allelic R264H mutation. Substitution of R-264 with histidine (R264H, the naturally occurring mutant), leucine (R264L), aspartic acid (R264D), or glutamic acid (R264E) greatly reduced MAT activity and severely impaired the ability of the MAT(alpha)1 subunits to form homodimers essential for optimal catalytic activity. On the other hand, when lysine was substituted for R-264 (R264K), the mutant alpha1 subunit was able to form dimers that retain significant MAT activity, suggesting that amino acid 264 is involved in intersubunit salt-bridge formation. Cotransfection studies show that R264/R264H MAT(alpha)1 heterodimers are enzymatically inactive, thus providing an explanation for the R264H-mediated dominant inheritance of hypermethioninemia.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hypermethioninemia  IAGP 1599915 RGD 
hypermethioninemia  ISOMAT1A (Homo sapiens)1599915; 1599915 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mat1a  (methionine adenosyltransferase 1A)

Genes (Mus musculus)
Mat1a  (methionine adenosyltransferase 1A)

Genes (Homo sapiens)
MAT1A  (methionine adenosyltransferase 1A)


Additional Information