PMID- 10484769
OWN - NLM
STAT- MEDLINE
DCOM- 19991216
LR  - 20190513
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 8
IP  - 11
DP  - 1999 Oct
TI  - Molecular basis for methionine synthase reductase deficiency in patients
      belonging to the cblE complementation group of disorders in folate/cobalamin
      metabolism.
PG  - 2009-16
AB  - 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.
FAU - Wilson, A
AU  - Wilson A
AD  - MRC Group in Medical Genetics, Montreal Children's Hospital, Canada.
FAU - Leclerc, D
AU  - Leclerc D
FAU - Rosenblatt, D S
AU  - Rosenblatt DS
FAU - Gravel, R A
AU  - Gravel RA
LA  - eng
GR  - HL58955-01/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (DNA, Complementary)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 935E97BOY8 (Folic Acid)
RN  - AE28F7PNPL (Methionine)
RN  - EC 1.18.1.- (methionine synthase reductase)
RN  - EC 1.18.1.2 (Ferredoxin-NADP Reductase)
RN  - EC 2.1.1.13 (5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase)
RN  - P6YC3EG204 (Vitamin B 12)
SB  - IM
MH  - 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase/deficiency/metabolism
MH  - Anemia, Megaloblastic/*genetics
MH  - DNA Mutational Analysis
MH  - DNA, Complementary/genetics
MH  - Enzyme Activation
MH  - Ferredoxin-NADP Reductase/*deficiency/genetics
MH  - Folic Acid/*metabolism
MH  - Genes, Recessive
MH  - Genetic Complementation Test
MH  - Heteroduplex Analysis
MH  - Homocysteine/metabolism
MH  - Humans
MH  - Hyperhomocysteinemia/*genetics
MH  - Methionine/metabolism
MH  - *Mutation
MH  - Polymorphism, Single-Stranded Conformational
MH  - RNA Splicing/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Sequence Analysis, DNA
MH  - Vitamin B 12/*genetics
EDAT- 1999/09/15 00:00
MHDA- 1999/09/15 00:01
CRDT- 1999/09/15 00:00
PHST- 1999/09/15 00:00 [pubmed]
PHST- 1999/09/15 00:01 [medline]
PHST- 1999/09/15 00:00 [entrez]
AID - ddc229 [pii]
AID - 10.1093/hmg/8.11.2009 [doi]
PST - ppublish
SO  - Hum Mol Genet. 1999 Oct;8(11):2009-16. doi: 10.1093/hmg/8.11.2009.