Human Molecular Genetics, Vol 8, 2009-2016, Copyright © 1999 by Oxford University Press
A Wilson, D Leclerc, DS Rosenblatt and RA Gravel
Methionine synthase reductase (MSR) deficiency is an autosomal recessive
disorder of folate/cobalamin metabolism leading to hyperhomocysteinemia,
hypo- methioninemia and megaloblastic anemia. Deficiency in MSR activity
occurs as the result of a defect in the MSR enzyme, which is required for
the reductive activation of methionine synthase (MS). MS itself is
responsible for the folate/cobalamin- dependent conversion of homo-
cysteine to methionine. We have recently cloned the cDNA corresponding to
the MSR protein, a novel member of the ferredoxin-NADP(+)reductase (FNR)
family of electron transferases. We have used RT-PCR, heteroduplex,
single-strand conformation poly- morphism (SSCP) and DNA sequence analyses
to reveal 11 mutations in eight patients from seven families belonging to
the cblE complementation group of patients of cobalamin metabolism that is
defective in the MSR protein. The mutations include splicing defects
leading to large insertions or deletions, as well as a number of smaller
deletions and point mutations. Apart from an intronic substitution found in
two unrelated patients, the mutations appear singular among individuals. Of
the eleven, three are nonsense mutations, allowing for the identification
of two patients for whom little if any MSR protein should be produced. The
remaining eight involve point mutations or in-frame disruptions of the
coding sequence and are distributed throughout the coding region, including
proposed FMN, FAD and NADPH binding sites. These data demonstrate a unique
requirement for MSR in the reductive activation of MS.
ARTICLES
Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism
MRC Group in Medical Genetics, Montreal Children's Hospital and.
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