Glutamate carboxypeptidase II: a polymorphism associated with lower levels of serum folate and hyperhomocysteinemia

• Published in: Human molecular genetics Vol. 9; no. 19; pp. 2837 - 2844
• Main Authors: DEVLIN, Angela M, LING, Erh-Hsin, PEERSON, Janet M, FERNANDO, Shama, CLARKE, Robert, SMITH, A. David, HALSTED, Charles H
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 22.11.2000; Oxford Publishing Limited (England)
• Subjects: Aged; Alleles; Alternative Splicing - genetics; Animals; Antigens, Surface; Biological and medical sciences; Carboxypeptidases - genetics; Carboxypeptidases - metabolism; Cloning, Molecular; COS Cells; DNA Mutational Analysis; European Continental Ancestry Group - genetics; folic acid; Folic Acid - blood; GCPII gene; glutamate carboxypeptidase; Glutamate Carboxypeptidase II; Homocysteine - blood; Humans; hyperhomocysteinemia; Hyperhomocysteinemia - blood; Hyperhomocysteinemia - genetics; Intestinal Absorption - genetics; Isoenzymes - genetics; Isoenzymes - metabolism; Jejunum - enzymology; Medical sciences; Metabolic diseases; Middle Aged; Miscellaneous; Molecular Sequence Data; Other metabolic disorders; Polymorphism, Genetic; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sequence Analysis, DNA; Transfection; Human; Glutamate carboxypeptidase II; Nucleotide sequence; Enzyme; Monkey; Gene expression; Folate; Kidney; Peptidases; Vertebrata; Metabolic disorder; Cell line; Mammalia; Gene; Aminoacid; DNA; Primates; Hydrolases; Metallocarboxypeptidases; Polymorphism
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/9.19.2837

Low blood folate levels result in hyperhomocysteinemia, which has been associated with increased risk for cardiovascular disease, neural tube defects and cognitive deficits. Intake of dietary folates is the chief determinant of blood folate levels. Molecular defects in the intestinal absorption of dietary folates that precipitate low blood folate levels and hyperhomocysteinemia have not been investigated previously. Dietary folates are a mixture of polyglutamylated folates which are digested to monoglutamyl folates by the action of folylpoly-gamma-glutamate carboxypeptidase (FGCP), an enzyme that is anchored to the intestinal brush border membrane and is expressed by the glutamate carboxypepidase II (GCPII) gene. We cloned GCPII cDNA from human intestine and identified both a full-length transcript and a 93 bp shorter transcript lacking exon 18, consistent with the presence of a splice variant. In addition, we identified an H475Y polymorphism in GCPII in DNA samples from a healthy Caucasian population (n = 75). We found that membranes of transfected COS-7 cells expressing the H475Y variant GCPII cDNA had 53% less FGCP activity than did cells expressing wild-type GCPII. The presence of the H475Y GCPII allele was significantly associated with lower folate and higher homocysteine levels in this population. These data suggest that the presence of the H475Y GCPII allele impairs the intestinal absorption of dietary folates, resulting in relatively low blood folate levels and consequent hyperhomocysteinemia.