ABSTRACT
We describe an 18-year-old patient with psychomotor retardation and abnormally short metatarsi and metacarpals but no other signs of classic Refsum disease. Molecular analysis of the phytanoyl-coenzyme A hydroxylase gene revealed a homozygous deletion causing a frameshift. Surprisingly, L-pipecolic acid was elevated in plasma, and microscopy of the liver showed a reduced number of peroxisomes per cell and a larger average peroxisome size. These abnormal peroxisomes lacked catalase as did peroxisomes in fibroblasts of this patient. Such generalized peroxisomal abnormalities are not present in classic Refsum disease.
Subject(s)
Metabolism, Inborn Errors/metabolism , Mixed Function Oxygenases/metabolism , Phytanic Acid/metabolism , Pipecolic Acids/metabolism , Refsum Disease/metabolism , Child , Female , Humans , Refsum Disease/enzymology , Refsum Disease/geneticsABSTRACT
The adrenoleukodystrophy gene encodes a peroxisomal integral membrane protein (ALDP) consisting of 745 amino acids with a molecular weight of 75kDa. ALDP expression was studied in fibroblasts from 24 male ALD patients from 17 unrelated ALD kindreds. In four kindreds an identical 2-base-pair deletion was found. We report the absence of ALDP in 12 kindreds carrying nonsense mutations, frame shifts or amino acid substitutions in the carboxy terminus of ALDP, together accounting for 71% of the ALD kindreds. ALDP was present in five kindreds (29%) with amino acid substitutions in the amino terminal half of the protein; in two of these kindreds ALDP was present although at a reduced level. The absence of truncated proteins suggests that the carboxy terminus has a function in the stabilization of ALDP.
Subject(s)
ATP-Binding Cassette Transporters/genetics , Adrenoleukodystrophy/genetics , Membrane Proteins/genetics , ATP Binding Cassette Transporter, Subfamily D, Member 1 , ATP-Binding Cassette Transporters/metabolism , Adrenoleukodystrophy/metabolism , Cell Line , Fibroblasts/metabolism , Frameshift Mutation , Gene Expression , Genetic Linkage , Humans , Male , Membrane Proteins/metabolism , Mutation , Phenotype , Point Mutation , Sequence Deletion , X ChromosomeABSTRACT
Mycophenolic acid, an inhibitor of the enzyme IMP dehydrogenase, antagonizes the CTP synthetase inhibitor 3-deazauridine in its anti-proliferative effects on MOLT-3 human T leukemia cells. No depletion of CTP occurred, and decreased amounts of 3-deazuridine-triphosphate were measured in cells incubated with mycophenolic acid and 3-deazuridine. Most probably, these phenomena are related to the increased amounts of PRPP observed, which can result in an increased pyrimidine biosynthesis de novo and, as a consequence, a decreased metabolism of 3-deazauridine via the salvage pathway.
