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Research article

Targeting and intracellular trafficking of clinically relevant hTHTR1 mutations in human cell lines

Veedamali S. Subramanian, Jonathan S. Marchant, Hamid M. Said
Clinical Science Jul 01, 2007, 113 (2) 93-102; DOI: 10.1042/CS20060331
Veedamali S. Subramanian
Department of Medicine, University of California, Irvine, CA 92697, U.S.A.Department of Physiology and Biophysics, University of California, Irvine, CA 92697, U.S.A.
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Jonathan S. Marchant
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, U.S.A.
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Hamid M. Said
Department of Medicine, University of California, Irvine, CA 92697, U.S.A.Department of Physiology and Biophysics, University of California, Irvine, CA 92697, U.S.A.Department of Veterans Affairs Medical Center, Long Beach, CA 90822, U.S.A.
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Abstract

The micronutrient thiamine is required for normal growth and development of human tissues, and is accumulated into cells through the activity of plasma membrane thiamine transporters, e.g. hTHTR1 (human thiamine transporter 1). Recent genetic evidence has linked mutations in hTHTR1 with the manifestation of TRMA (thiamine-responsive megaloblastic anaemia), a condition also associated with diabetes mellitus, sensorineural deafness and retinal disorders. To examine how mutations in hTHTR1 impair thiamine accumulation, we have investigated the targeting and functional properties of several different hTHTR1 mutants in human cell lines derived from epithelia relevant to thiamine absorption or tissues implicated in TRMA pathology. These constructs encompassed two newly identified point mutations (P51L and T158R) and two truncations of hTHTR1 identical with those found in TRMA kindreds (W358X and Δ383fs). Our results reveal a spectrum of mutant phenotypes, underlining that TRMA can result from decreased thiamine transport activity underpinned by changes in hTHTR1 expression levels, cellular targeting and/or protein transport activity.

  • cellular targeting
  • human thiamine transporter (hTHTR)
  • micronutrient
  • thiamine
  • thiamine-responsive megaloblastic anaemia (TRMA)
  • transporter
  • vitamin

Abbreviations: DMEM, Dulbecco's modified Eagle's medium; DsRed2, Discosoma sp. red fluorescent protein 2; DsRed2-ER, DsRed2 targeted to the endoplasmic reticulum; FM4-64, N-(3-triethylammoniumpropyl)-4-(6-(4-diethylamino)phenyl)-hexatrienyl)pyridinium dibromide; GFP, green fluorescent protein; HEK-293 cell, human embryonic kidney cell; hSVCT1, human sodium-dependent vitamin C transporter 1; hTHTR, human thiamine transporter; MEM, minimal essential medium; RT-PCR, reverse transcriptase-PCR; TRMA, thiamine-responsive megaloblastic anaemia; 3D, three-dimensional; V1aR, rat vasopressin receptor

  • © The Authors Journal compilation © 2007 Biochemical Society
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July 2007

Volume: 113 Issue: 2

Clinical Science: 113 (2)
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Targeting and intracellular trafficking of clinically relevant hTHTR1 mutations in human cell lines
Veedamali S. Subramanian, Jonathan S. Marchant, Hamid M. Said
Clinical Science Jul 2007, 113 (2) 93-102; DOI: 10.1042/CS20060331
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Targeting and intracellular trafficking of clinically relevant hTHTR1 mutations in human cell lines
Veedamali S. Subramanian, Jonathan S. Marchant, Hamid M. Said
Clinical Science Jul 2007, 113 (2) 93-102; DOI: 10.1042/CS20060331

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Keywords

cellular targeting
human thiamine transporter (hTHTR)
micronutrient
thiamine
thiamine-responsive megaloblastic anaemia (TRMA)
transporter
vitamin

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