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Rapid CommunicationShort Communication

A Rare UGT2B7 Variant Creates a Novel N-Glycosylation Site at Codon 121 with Impaired Enzyme Activity

Camille Girard-Bock, Marie-Odile Benoit-Biancamano, Lyne Villeneuve, Sylvie Desjardins and Chantal Guillemette
Drug Metabolism and Disposition December 2016, 44 (12) 1867-1871; DOI: https://doi.org/10.1124/dmd.116.071860
Camille Girard-Bock
Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec City (C.G.B., L.V., S.D., C.G.), and Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, (M.O.B.B.), Québec, Canada
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Marie-Odile Benoit-Biancamano
Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec City (C.G.B., L.V., S.D., C.G.), and Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, (M.O.B.B.), Québec, Canada
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Lyne Villeneuve
Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec City (C.G.B., L.V., S.D., C.G.), and Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, (M.O.B.B.), Québec, Canada
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Sylvie Desjardins
Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec City (C.G.B., L.V., S.D., C.G.), and Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, (M.O.B.B.), Québec, Canada
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Chantal Guillemette
Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec City (C.G.B., L.V., S.D., C.G.), and Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, (M.O.B.B.), Québec, Canada
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Abstract

The UDP glucuronosyltransferase (UGT) superfamily comprises glycoproteins that reside in the endoplasmic reticulum membranes and that undergo post-translational modifications (PTMs). UGT2B7 is of particular interest because of its action on a wide variety of drugs. Most studies currently survey common variants and examine only a small fraction of the genetic diversity; however, rare variants (frequency <1%) might have a significant effect because they are predicted to greatly outnumber common variants in the human genome. We discovered a rare single nucleotide UGT2B7 variant of potential pharmacogenetic relevance that encodes a nonconservative amino acid substitution at codon 121. This low-frequency variation, found in two individuals of a population of 305 healthy volunteers, leads to the translation of an asparagine instead of an aspartic acid (UGT2B7 p.D121N). This amino acid change was predicted to create a putative N-glycosylation motif NX(S/T) subsequently validated upon endoglycosidase H treatment of microsomal fractions and inhibition of N-glycosylation of endogenously produced UGT2B7 with tunicamycin in human embryonic kidney (HEK293) cells. The presence of an additional N-linked glycan on the UGT2B7 enzyme, likely affecting proper protein folding, resulted in a significant decrease of 49% and 40% in the formation of zidovudine and mycophenolic acid glucuronides, respectively. A systematic survey of the Short Genetic Variations database uncovered 32 rare, naturally occurring missense variations predicted to create or disrupt N-glycosylation sequence motifs in the other UGT2B enzymes. Collectively, these variants have the potential to increase the proportion of variance explained in the UGT pathway resulting from changes in PTMs, such as N-linked glycosylation with consequences on drug metabolism.

Footnotes

    • Received May 31, 2016.
    • Accepted September 8, 2016.
  • This work is supported by the Canadian Institutes of Health (Grant CIHR MOP-42392). CGB received studentships from the Fonds d’enseignement et de recherche (FER) of Laval University’s Faculty of Pharmacy and from the Fondation Desjardins and Fondation du Centre Hospitalier Universitaire de Québec. C.G. holds a Canada Research Chair in Pharmacogenomics (Canadian Research Chair Program).

  • dx.doi.org/10.1124/dmd.116.071860.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (12)
Drug Metabolism and Disposition
Vol. 44, Issue 12
1 Dec 2016
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Rapid CommunicationShort Communication

A Rare Functional UGT2B7 D121N Variant

Camille Girard-Bock, Marie-Odile Benoit-Biancamano, Lyne Villeneuve, Sylvie Desjardins and Chantal Guillemette
Drug Metabolism and Disposition December 1, 2016, 44 (12) 1867-1871; DOI: https://doi.org/10.1124/dmd.116.071860

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Rapid CommunicationShort Communication

A Rare Functional UGT2B7 D121N Variant

Camille Girard-Bock, Marie-Odile Benoit-Biancamano, Lyne Villeneuve, Sylvie Desjardins and Chantal Guillemette
Drug Metabolism and Disposition December 1, 2016, 44 (12) 1867-1871; DOI: https://doi.org/10.1124/dmd.116.071860
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