Identification of four novel mutations in severe methylenetetrahydrofolate reductase deficiency.
Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is an inborn error of folate metabolism, and is inherited as an autosomal recessive trait. MTHFR is a key enzyme in folate-dependent remethylation of homocysteine, and reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Patients with this severe enzymatic deficiency are biochemically characterised by homocystinuria and hypomethioninaemia, and may suffer from neurological abnormalities, mental retardation and premature vascular disease. Here we report the molecular basis of severe MTHFR deficiency in four unrelated families from Turkish/Greek ancestry. By use of reverse-transcriptase (RT)-PCR, subsequently followed by direct sequencing analysis, we were able to identify four novel mutations in the MTHFR gene: two missense (983A-->G; 1027T-->G) and two nonsense (1084C-->T; 1711C-->T) mutations. Furthermore, a splice variant containing a premature termination codon, was observed in one patient, probably as a secondary effect of the 1027T-->G missense mutation. The ongoing identification and characterisation of mutations in the MTHFR gene will provide further insight into the heterogeneity of the clinical phenotype in severe MTHFR deficiency.
Department of Pediatrics, University Hospital Nijmegen, The Netherlands.
L A
LA
Kluijtmans
U
U
Wendel
E M
EM
Stevens
L P
LP
van den Heuvel
F J
FJ
Trijbels
H J
HJ
Blom
D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D017931:DNA Primers; D005260:Female; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008969:Molecular Sequence Data; D009154:Mutation; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000172:deficiency / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)