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Disruption of Transport Activity in a D93H Mutant Thiamine Transporter 1, from a Rogers Syndrome Family

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Disruption of Transport Activity in a D93H Mutant Thiamine Transporter 1, from a Rogers Syndrome Family Eur. J. Biochem. 270, 4469–4477 (2003) Ó FEBS2003 doi:10.1046/j.1432-1033.2003.03839.x Disruption of transport activity in a D93H mutant thiamine transporter 1, from a Rogers Syndrome family Dana Baron1, Yehuda G. Assaraf2, Stavit Drori2 and Ami Aronheim1 1Department of Molecular Genetics, The Rappaport Institute for Research in the Medical Sciences and the B. Rappaport Faculty of Medicine, and 2Department of Biology, The Technion-Israel Institute of Technology, Haifa, Israel Rogers syndrome is an autosomal recessive disorder result- transport null cells of a homologous D88H mutation in ing in megaloblastic anemia, diabetes mellitus, and sensori- the hRFC did not result in restoration of MTX trans- neural deafness. The gene associated with this disease port activity, thereby suggesting that D88 is an essential encodes for thiamine transporter 1 (THTR1), a member of residue for MTX transport activity. These results suggest the SLC19 solute carrier family including THTR2 and the that the D93H mutation does not interfere with trans- reduced folate carrier (RFC). Using transient transfections porter expression, glycosylation and plasma membrane into NIH3T3 cells of a D93H mutant THTR1 derived targeting. However, the substitution of this negatively from a Rogers syndrome family, we determined the charged amino acid (Asp93) by a positively charged expression, post-translational modification, plasma mem- residue (His) in an extremely conserved region (the bor- brane targeting and thiamine transport activity. We also der of transmembrane domain 2/intracellular loop 2) in explored the impact on methotrexate (MTX) transport the SLC19 family, presumably inflicts deleterious struc- activity of a homologous missense D88H mutation in the tural alterations that abolish thiamine binding and/or human RFC, a close homologue of THTR1. Western blot translocation. Hence, this functional characterization analysis revealed that the D93H mutant THTR1 was nor- of the D93H mutation provides a molecular basis for mally expressed and underwent a complete N-glycosylation. Rogers syndrome. However, while this mutant THTR1 was targeted to the Keywords: Rogers syndrome; thiamine; transporter; muta- plasma membrane, it was completely devoid of thiamine tions. transport activity. Consistently, introduction into MTX Thiamine responsive megaloblastic anemia (TRMA) also progression, insulin secretion gradually declines to levels known as Rogers syndrome [1], is an early onset autosomal that require insulin therapy. On the other hand, in all recessive disorder that was described in only 20 families TRMA patients, anemia is fully reversed following the all over the world. Patients with Rogers syndrome are administration of high doses of thiamine [5]. diagnosed by the occurrence of multiple clinical manifesta- Fibroblasts isolated from Rogers syndrome patients, tions including: megaloblastic anemia, diabetes mellitus and display only 5–10% of thiamine uptake as compared with sensorineural deafness [Online Mendelian Inheritance in fibroblasts derived from healthy individuals. This uptake Man (OMIM) 249270, http://www.ncbi.nlm.nih.gov/ apparently occurs via a low-affinity, unsaturable thiamine Omim/]. The administration of high doses of thiamine or route [6]. These results are consistent with an entry of alternatively the use of medications such as sulfonylureas thiamine via passive diffusion and may explain the fact that recovers insulin secretion [2–4]. However, with disease high doses of thiamine are able to induce minimally sufficient thiamine levels in Rogers syndrome patients. The gene responsible for Rogers syndrome, SLC19A2, Correspondence to A. Aronheim, Department of Molecular Genetics, was identified by positional cloning [7–9]. SLC19A2 encodes The B. Rappaport Faculty of Medicine, 7th Efron St. Bat-Galim, for a thiamine transporter (THTR1), a member of the solute The Technion-Israel Institute of Technology, Haifa 31096, Israel. carrier family. This family includes SLC19A1 that encodes Fax: + 972 4 8295225, Tel.: + 972 4 8295226, for the reduced folate carrier (RFC) and SLC19A3 that E-mail: [email protected] encodes for thiamine transporter 2, THTR2 [10]. THTR1 Y. G. Assaraf, Department of Biology, The Technion-Israel contains 497-amino acids and has 12 putative transmem- Institute of Technology, Haifa 32000, Israel. brane domains (TMD) [7–9]. THTR1 is responsible for + Fax: + 972 4 8225153, Tel.: + 972 4 8293744, thiamine transport in a Na independent manner and is + E-mail: [email protected] stimulated by H efflux gradient [11]. Abbreviations: DMEM, Dulbecco’s modified Eagle’s medium; MTX, Although all Rogers syndrome patients exhibit similar Methotrexate; THTR1, thiamine transporter 1; TRMA, thiamine clinical manifestations, multiple mutations were identified responsive megaloblastic anemia; hRFC, human reduced folate resulting in premature translation termination due to base carrier; TMD, transmembrane domain. pair insertions or deletions which result in frame-shift. In (Received 23 July 2003, revised 11 September 2003, addition, three missense mutations were described resulting accepted 18 September 2003) in single amino-acid substitutions. Recently we have initiated 4470 D. Baron et al.(Eur. J. Biochem. 270) Ó FEBS2003 studies that are aimed at characterization of the impact BRL Inc.), whereas XtremeGENE reagent (Roche Inc.) was that these missense THTR1 mutations have on the expres- used for Swiss 3T3 cells. Typically, for NIH3T3 cell sion, post-translational modification, plasma membrane transfections, 6 lg of plasmid DNA were used with 9 lL targeting and thiamine transport activity. In a recent paper, of the LipofectAMINE reagent whereas for Swiss 3T3 cells, we described the molecular consequences of a single amino- 2 lg of plasmid DNA were used along with 10 lLof acid substitution identified in an Italian Rogers syndrome XtremeGENE reagent according to the instructions of the family harboring a glycine to aspartate substitution at manufacturer. position 172 of the THTR1 [12]. Although this mutant THTR1 gene is properly transcribed and translated in vitro, Cell extract no protein could be detected in NIH3T3 cells transfected with the mutant G172D THTR1 cultured at 37 °C. Shifting Whole cell extracts were isolated as previously described transfected cells to 28 °C resulted in a substantial expression [17]. of the mutant G172D THTR1 protein thereby allowing for biochemical and functional characterization [12]. The Isolation of THTR1 cDNA G172D mutant THTR1 failed to undergo a complete N-glycosylation, on the glutamine 63 acceptor which is THTR1 cDNA was isolated as previously described [12]. found to be conserved in both THTR1 and THTR2 [12] resulting in its cytoplasmic retention in the endoplasmic Mammalian expression plasmids reticulum. This is in contrast to the other members of the solute carrier family, including the hRFC, in which pCan-THTR1 expression plasmids; pCan is a pcDNA- N-glycosylation plays neither a role in its plasma membrane based (Invitrogen Inc.) mammalian expression vector localization nor in MTX transport activity [13]. Here we expressing proteins downstream of a Myc-epitope tag. describe the characterization of another mutation identified Protein expression is under the control of cytomegalovirus in a French Rogers family harboring an aspartate to (CMV) immediate early promoter. An oligonucleotide histidine substitution at position 93 (D93H) in THTR1 [14]. based PCR approach was used to amplify the human Unlike in a previous analysis of the D93H mutation [15], THTR1 cDNA that was fused, in frame, with the Myc- here we show that the mutant protein was efficiently epitope tag using 5¢-EcoRI and 3¢-XhoI restriction sites. The expressed both in vitro and in vivo and upon immunoflu- Myc tag and polylinker regions are composed of the orescence studies this protein was properly targeted to the following 17 amino acids: MVQKLISEEDLRIHRCR. For plasma membrane. Uptake studies with the D93H mutant fusion of Myc tag to the C-terminus of the THTR1, an protein revealed no [3H]thiamine transport activity. Import- oligonucleotide-based PCR approach was used to amplify antly, this D93 region in THTR1 and the homologous D88 the human THTR1 cDNA that was fused in frame, using vicinity in the hRFC are extremely conserved among all 5¢-HindIII and 3¢-HindIII restriction sites with the Myc tag members of the solute carrier family (SLC19A1, SLC19A2 in the 3¢-end. The correct orientation was verified by XbaI and SLC19A3). Indeed, a hRFC harboring the same D88H digestion generating a 1100-bp fragment due to a unique mutation displayed no methotrexate transport activity. This XbaI site at position 377 within THTR1 cDNA and at is consistent with a previous report in which a D88V mutant the 3¢-end of the pCan expression vector’s multiple cloning RFC showed no transport activity [16]. We suggest that this site. site (i.e. D93 in THTR1 and D88 in hRFC) represents a highly conserved region, which is absolutely essential for the GFP expression plasmid structure and function of all members of the solute carrier family. Hence, the present study constitutes the first This plasmid encodes for the green fluorescent protein under demonstration of a THTR1 mutation that does not interfere the control of the CMV promoter (Life Technologies Inc.). with transporter expression, N-linked glycosylation and plasma membrane targeting but completely disrupts thi- Site-directed mutagenesis amine transport activity. The corresponding oligonucleotides were designed to
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