Human Molecular Genetics, Vol 5, 1859-1865, Copyright © 1996 by Oxford University Press
S Gulati, P Baker, YN Li, B Fowler, W Kruger, LC Brody and R Banerjee
Inborn errors resulting in isolated functional methionine synthase
deficiency fall into two complementation groups, cblG and cblE. Using
biochemical approaches we demonstrate that one cblG patient has greatly
reduced levels of methionine synthase while in another, the enzyme is
specifically impaired in the reductive activation cycle. The biochemical
data suggested that low levels of methionine synthase activity in the first
patient may result from mutations in the catalytic domains of the enzyme,
reduced transcription, or generation of unstable message or protein. Using
Northern analysis, we demonstrate that the molecular basis for the
biochemical phenotype in this patient is associated with greatly diminished
steady-state levels of methionine synthase mRNA. The biochemical data on
the second patient cell line implicated mutations specific to reductive
activation, a function that is housed in the C-terminal AdoMet-binding
domain and the intermediate B12-binding domain, in the highly homologous
bacterial enzyme. We have detected two mutations in a compound heterozygous
state, one that results in conversion of a conserved proline (1173) to a
leucine residue and the other a deletion of an isoleucine residue (881).
The crystal structure of the C-terminal domain of the Escherichia coli MS
predicts that the Pro to Leu mutation could disrupt activation since it is
embedded in a sequence that makes direct contacts with the bound AdoMet.
Deletion of isoleucine in the B12-binding domain would result in shortening
of a beta-sheet. Our data provide the first evidence for mutations in the
methionine synthase gene being culpable for the cblG phenotype. In
addition, they suggest directly that mutations in methionine synthase can
lead to elevated homocysteine, implicated both in neural tube defects and
in cardiovascular diseases.
ARTICLES
Defects in human methionine synthase in cblG patients
Biochemistry Department, University of Nebraska, Lincoln 68588-0664, USA.
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