A novel variant L263F in human inosine 5'-monophosphate dehydrogenase 2 is associated with diminished enzyme activity.

A novel variant L263F in human inosine 5'-monophosphate dehydrogenase 2 is associated with diminished enzyme activity. Research Abstract Details 

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A novel variant L263F in human inosine 5'-monophosphate dehydrogenase 2 is associated with diminished enzyme activity. Abstract Text:

Jian Wang,Adriana Zeevi,Steve Webber,Diana M Girnita,Linda Addonizio,Rick Selby,Ian V Hutchinson,Gilbert J Burckart,

BACKGROUND AND OBJECTIVE: Inosine 5'-monophosphate dehydrogenase 2 is required for purine synthesis in activated lymphocytes. Variants in the IMPDH2 gene may account for the large inter-individual variability in baseline enzyme activity, immunosuppressive efficacy and side effects in transplant recipients receiving mycophenolic acid. Therefore, the objective of this study was to identify and functionally characterize IMPDH2 variants. METHODS: DNA samples from 152 solid organ transplant patients were screened at exons and exon/intron junctions of the IMPDH2 genes by PCR amplification followed by bidirectional direct DNA sequencing. Genetic variant was constructed by site-directed mutagenesis and transformed to an inosine 5'-monophosphate dehydrogenase-deficient strain of Escherichia coli h712. Proteins were purified to homogeneity and the enzymatic activity was measured by reduced nicotinamide adenine dinucleotide production. RESULTS: Nine genetic variants were identified in the IMPDH2 gene, with frequencies of the rarer alleles ranging from 0.5 to 10.2%. A novel nonsynonymous variant L263F was identified, and the kinetic assay demonstrated that the inosine 5'-monophosphate dehydrogenase activity of L263F variant was decreased to 10% of the wild-type. The Ki for mycophenolic acid inhibition of the L263F variant was comparable with the wild-type, and the variant Km for inosine 5'-monophosphate and nicotinamide adenine dinucleotide did not change significantly. CONCLUSIONS: IMPDH2 has low genetic diversity, but the nonsynonymous variant L263F has a significant impact on inosine 5'-monophosphate dehydrogenase activity. This novel functional variant may be one of the factors contributing to the inter-individual difference of baseline inosine 5'-monophosphate dehydrogenase activity as well as drug efficacy and adverse events in transplant patients.

A novel variant L263F in human inosine 5'-monophosphate dehydrogenase 2 is associated with diminished enzyme activity. Publishing Authors By Initials

J Wang,A Zeevi,S Webber,DM Girnita,L Addonizio,R Selby,IV Hutchinson,GJ Burckart,

For similar genetic phenomena: variation (genetics) research abstracts see: genetic phenomena: variation (genetics) research

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A novel variant L263F in human inosine 5'-monophosphate dehydrogenase 2 is associated with diminished enzyme activity. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Pharmacogenetics and genomics

VOLUME: 17

Page Numbers: 283-90

Journal Abbreviation: Pharmacogenet. Genomics

ISSN: 1744-6872

DAY: 3

MONTH: Apr

YEAR: 2007

A novel variant L263F in human inosine 5'-monophosphate dehydrogenase 2 is associated with diminished enzyme activity. Information

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LANGUAGE: eng

NlmUniqueID: 101231005

A novel variant L263F in human inosine 5'-monophosphate dehydrogenase 2 is associated with diminished enzyme activity. Keywords Mesh Terms:

KEYWORDS: Variation (Genetics)

MESH TERMS: genetics

Chemical & Substance for Abstract: A novel variant L263F in human inosine 5'-monophosphate dehydrogenase 2 is associated with diminished enzyme activity. Information

Substance Name: IMPDH2 protein, human

Registry Number: EC 1.1.1.205

Grant and Affiliation Information for A novel variant L263F in human inosine 5'-monophosphate dehydrogenase 2 is associated with diminished enzyme activity.

AFFILIATION: Department of Pharmacy, University of Southern California, Los Angeles, California 90033, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: 5P50 HL074732

ACRONYM: HL

MEDLINETA: Pharmacogenet Genomics

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