| 1. |
- Anandapadmanaban, Madhanagopal, et al.
(författare)
-
High-resolution structure of TBP with TAF1 reveals anchoring patterns in transcriptional regulation
- 2013
-
Ingår i: Nature Structural & Molecular Biology. - : NATURE PUBLISHING GROUP, 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA. - 1545-9993 .- 1545-9985. ; 20:8, s. 1008-
-
Tidskriftsartikel (refereegranskat)abstract
- The general transcription factor TFIID provides a regulatory platform for transcription initiation. Here we present the crystal structure (1.97 angstrom) and NMR analysis of yeast TAF1 N-terminal domains TAND1 and TAND2 bound to yeast TBP, together with mutational data. We find that yeast TAF1-TAND1, which in itself acts as a transcriptional activator, binds TBPs concave DNA-binding surface by presenting similar anchor residues to TBP as does Mot1 but from a distinct structural scaffold. Furthermore, we show how TAF1-TAND2 uses an aromatic and acidic anchoring pattern to bind a conserved TBP surface groove traversing the basic helix region, and we find highly similar TBP-binding motifs also presented by the structurally distinct TFIIA, Mot1 and Brf1 proteins. Our identification of these anchoring patterns, which can be easily disrupted or enhanced, provides insight into the competitive multiprotein TBP interplay critical to transcriptional regulation.
|
|
| 2. |
- Andrésen, Cecilia, et al.
(författare)
-
Molecular characterization of the interaction between the disordered c-Myc transactivation domain and the TATA-binding protein (TBP)
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The proto-oncogene c-myc affects the occurrence, expansion, and evolution of numerous aggressive human cancers, and is often associated with the late-stage and/or poor prognostic disease. Regulation of target gene activity by c-Myc occurs through protein interactions with the c-Myc transactivation domain (TAD) which, in addition to binding the TATA-binding protein (TBP) also recruits a wide variety of co-activators and suppressor proteins. Here, we present a molecular model, based on NMR, X-ray crystallography and SPR measurements, which describes how the c-Myc TAD binds to TBP. Our model contributes to the understanding of how c-Myc can regulate individual genes as well as entire gene programs.
|
|
| 3. |
- Andrésen, Cecilia, et al.
(författare)
-
Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding
- 2012
-
Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP): Policy C / Oxford University Press. - 0305-1048 .- 1362-4962. ; 40:13, s. 6353-6366
-
Tidskriftsartikel (refereegranskat)abstract
- The crucial role of Myc as an oncoprotein and as a key regulator of cell growth makes it essential to understand the molecular basis of Myc function. The N-terminal region of c-Myc coordinates a wealth of protein interactions involved in transformation, differentiation and apoptosis. We have characterized in detail the intrinsically disordered properties of Myc-1-88, where hierarchical phosphorylation of S62 and T58 regulates activation and destruction of the Myc protein. By nuclear magnetic resonance (NMR) chemical shift analysis, relaxation measurements and NOE analysis, we show that although Myc occupies a very heterogeneous conformational space, we find transiently structured regions in residues 22-33 and in the Myc homology box I (MBI; residues 45-65); both these regions are conserved in other members of the Myc family. Binding of Bin1 to Myc-1-88 as assayed by NMR and surface plasmon resonance (SPR) revealed primary binding to the S62 region in a dynamically disordered and multivalent complex, accompanied by population shifts leading to altered intramolecular conformational dynamics. These findings expand the increasingly recognized concept of intrinsically disordered regions mediating transient interactions to Myc, a key transcriptional regulator of major medical importance, and have important implications for further understanding its multifaceted role in gene regulation.
|
|
| 4. |
- Andrésen, Cecilia, et al.
(författare)
-
Transient structure and intrinsic disorder in the c-Myc transactivation domain and its effects on ligand binding
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The crucial role of c-Myc as an oncoprotein and as a key regulator of cell growth makes it essential to understand the molecular basis of c-Myc function. The transactivation domain of c-Myc coordinates a wealth of protein interactions involved in transformation, differentiation and apoptosis. We have characterized in detail the intrinsically disordered properties of c-Myc-1-88, where hierarchical phosphorylation of T58 and S62 regulates activation and destruction of the c-Myc protein. By NMR chemical shift analysis, relaxation measurements and NOE analysis, we show that both the MBI region (residues 45-65) and residues 22-33 are transiently structured regions, conserved also in other members of the Myc family. Binding of Bin1-SH3 to c-Myc-1-88 as assayed by NMR and SPR revealed primary binding to the S62 region, but also a dynamically disordered and multivalent complex in which intrinsic disorder of c-Myc-1-88 was retained while releasing transient intramolecular interactions. Our findings describe a novel mode of regulatory recognition of c-Myc that is in agreement with the increasingly recognized capability of intrinsically disordered regions to efficiently mediate transient interactions with a wide range of targets, with important implications towards understanding the unique multifaceted biological functions of c-Myc.
|
|
| 5. |
- Carmont, Michael R, 1972, et al.
(författare)
-
The release of adhesions improves outcome following minimally invasive repair of Achilles tendon rupture
- 2022
-
Ingår i: Knee Surgery Sports Traumatology Arthroscopy. - : Springer Science and Business Media LLC. - 0942-2056 .- 1433-7347. ; 30, s. 1109-1117
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose Operative repair of Achilles tendon rupture may lead to complications, which influence outcome adversely. The aim of this study was to determine the incidence, impact and response to treatment of post-operative adhesions. Methods From February 2009 to 2021, 248 patients operated on with percutaneous or minimally invasive surgical repair have been prospectively evaluated using the Achilles tendon Total Rupture Score (ATRS) and Heel-Rise Height Index (HRHI), following acute Achilles tendon rupture. Results Fourteen (5.6%) patients were identified as having adhesions. Four patients reported superficial adhesions and ten patients reported a deeper tightness of the tendon. At a mean (SD) of 10.5 (2.3) months following repair, the overall ATRS was at a median (IQR) 65 (44.5-78) points and (HRHI) was mean (SD) 81.5 (13.5)%. Of those deemed to have deep adhesions the antero-posterior diameter of the tendon was at mean (SD) 15.6 (4.6) mm. Open release of superficial adhesions resulted in improved ATRS in all patients. Endoscopic debridement anterior to the Achilles tendon led to alleviation of symptoms of tightness and discomfort from deep adhesions and improved outcome in terms of the ATRS score. At a mean (SD) of 15.9 (3.3)-month follow-up from initial rupture and repair, the patients reported at median (IQR) ATRS scores of 85 (64.8-92.8) points, Tegner level 5 (3-9) and mean (SD) HRHI 86.2 (9.5)%. Patients significantly improved both ATRS and HRHI following release at median (IQR) of 16.5 (- 1.8-29.3) points (p = 0.041) and mean (SD) 5.6 (8.3)% (p = 0.043). Conclusions The incidence of patient-reported adhesions following minimally invasive repair of Achilles tendon rupture was estimated to be 5.6%. The occurrence of superficial adhesions was associated with a lower outcome scores as well as symptoms of anterior tendon tightness and stiffness were associated with a lower score in most patients. Surgical release of adhesions led to a significant improvement in outcome.
|
|
| 6. |
- Ewert, Sara, 1974, et al.
(författare)
-
The bradykinin BK2 receptor mediates angiotensin II receptor type 2 stimulated rat duodenal mucosal alkaline secretion.
- 2003
-
Ingår i: BMC physiology. - 1472-6793. ; 3
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: This study investigates bradykinin and nitric oxide as potential mediators of AT2-receptor-stimulated duodenal mucosal alkaline secretion. Duodenal mucosal alkaline secretion was measured in methohexital- and alpha-chloralose-anaesthetised rats by means of in situ pH-stat titration. Immunohistochemistry and Western blot were used to identify the BK2 receptors. RESULTS: The AT2 receptor agonist CGP42112A (0.1 microg kg(-1) min(-1)) administered intravenously increased the duodenal mucosal alkaline secretion by approximately 50 %. This increase was sensitive to the selective BK2 receptor blocker HOE140 (100 ng/kg i.v.), but not to luminal administration of the NOS blocker L-NAME (0.3 mM). Mean arterial pressure did not differ between groups during the procedures. Immunohistochemistry showed a distinct staining of the crypt epithelium and a moderate staining of basal cytoplasm in villus enterocytes. CONCLUSION: The results suggest that the AT2-receptor-stimulated alkaline secretion is mediated via BK2 receptors located in the duodenal cryptal mucosal epithelium.
|
|
| 7. |
- Faxneld, Suzanne, et al.
(författare)
-
Temporal Trends and Geographical Differences of Perfluoroalkyl Acids in Baltic Sea Herring and White-Tailed Sea Eagle Eggs in Sweden
- 2016
-
Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 50:23, s. 13070-13079
-
Tidskriftsartikel (refereegranskat)abstract
- Temporal and spatial trends of perfluoroalkyl acids (PFAAs) were investigated in Baltic Sea herring liver (Clupea harengus) from three sites, and white-tailed sea eagle (WTSE) eggs (Haliaeetus albicilla) from two freshwater and two marine areas in Sweden. Trends of most quantifiable PFAAs increased over the monitored period (1980-2014 in herring, 1960s/1980s-2010 in WTSE). No significant decreasing trends were observed for the most recent ten years for any substances, except perfluorooctane sulfonamide (FOSA). Concentrations of perfluorooctanesulfonic acids (PFOS) in herring showed a distinct decreasing spatial trend moving from the more southern site toward the more northern site, indicating main input of PFOS into the southern Baltic Sea. For WTSE, PFOS concentration was higher in the marine compared to the freshwater environment, explained by the cumulative historic contamination of the Baltic Sea. Similarly, concentrations in WTSE were lower in the northern part of the Baltic Sea compared to further south. Concentrations of PFUnDA, representing long-chain perfluoroalkyl carboxylic acids (PFCAs), showed a more homogeneous spatial distribution compared to PFOS for both herring and WTSE, indicating that atmospheric inputs (via precursors) of the long-chain PFCAs are important contributors in the study areas.
|
|
| 8. |
- Helander, Sara, et al.
(författare)
-
Basic Tilted Helix Bundle - A new protein fold in human FKBP25/FKBP3 and HectD1
- 2014
-
Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier. - 0006-291X .- 1090-2104. ; 447:1, s. 26-31
-
Tidskriftsartikel (refereegranskat)abstract
- In this paper, we describe the structure of a N-terminal domain motif in nuclear-localized FKBP251-73, a member of the FKBP family, together with the structure of a sequence-related subdomain of the E3 ubiquitin ligase HectD1 that we show belongs to the same fold. This motif adopts a compact 5-helix bundle which we name the Basic Tilted Helix Bundle (BTHB) domain. A positively charged surface patch, structurally centered around the tilted helix H4, is present in both FKBP25 and HectD1 and is conserved in both proteins, suggesting a conserved functional role. We provide detailed comparative analysis of the structures of the two proteins and their sequence similarities, and analysis of the interaction of the proposed FKBP25 binding protein YY1. We suggest that the basic motif in BTHB is involved in the observed DNA binding of FKBP25, and that the function of this domain can be affected by regulatory YY1 binding and/or interactions with adjacent domains.
|
|
| 9. |
- Helander, Sara, et al.
(författare)
-
Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity
- 2015
-
Ingår i: Structure. - : Cell Press. - 0969-2126 .- 1878-4186. ; 23:12, s. 2267-2279
-
Tidskriftsartikel (refereegranskat)abstract
- Hierarchic phosphorylation and concomitant Pin1-mediated proline isomerization of the oncoprotein c-Myc controls its cellular stability and activity. However, the molecular basis for Pin1 recognition and catalysis of c-Myc and other multisite, disordered substrates in cell regulation and disease is unclear. By nuclear magnetic resonance, surface plasmon resonance, and molecular modeling, we show that Pin1 subdomains jointly pre-anchor unphosphorylated c-Myc1–88 in the Pin1 interdomain cleft in a disordered, or “fuzzy”, complex at the herein named Myc Box 0 (MB0) conserved region N-terminal to the highly conserved Myc Box I (MBI). Ser62 phosphorylation in MBI intensifies previously transient MBI-Pin1 interactions in c-Myc1–88 binding, and increasingly engages Pin1PPIase and its catalytic region with maintained MB0 interactions. In cellular assays, MB0 mutated c-Myc shows decreased Pin1 interaction, increased protein half-life, but lowered rates of Myc-driven transcription and cell proliferation. We propose that dynamic Pin1 recognition of MB0 contributes to the regulation of c-Myc activity in cells
|
|
| 10. |
- Helander, Sara, 1981-
(författare)
-
Structural biology of transcriptional regulation in the c-Myc network
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The oncogene c-‐Myc is overexpressed in many types of human cancers and regulation of c-‐Myc expression is crucial in a normal cell. The intrinsically disordered N-‐terminal transactivation domain interacts with a wide range of proteins regulating c-‐Myc activity. The highly conserved Myc box I region includes residues Thr58 and Ser62, which are involved in the phosphorylation events that control c-‐Myc degradation by ubiquitination. Aggressive cell growth, leading to tumor formation, occurs if activated c-‐ Myc is not degraded by ubiquitination. Such events may be triggered by defects in the regulated network of interactions involving Pin1 and phospho-‐dependent kinases.In this thesis, the properties of the intrinsically disordered unphosphorylated c-‐Myc1-‐88 and its interaction with Bin1 are studied by nuclear magnetic resonance (NMR) spectroscopy and surface plasmon resonance (SPR). Furthermore, the interaction of Myc1-‐88 with Pin1 is analyzed in molecular detail, both for unphosphorylated and Ser62 phosphorylated c-‐Myc1-‐88, providing a first molecular description of a disordered but specific c-‐Myc complex. A detailed analysis of the dynamics and structural properties of the transcriptional activator TAF in complex with TBP, both by NMR spectroscopy and crystallography, provides insight into transcriptional regulation and how c-‐Myc could interact with TBP. Finally, the structure of a novel N-‐terminal domain motif in FKBP25, which we name the Basic Tilted Helix Bundle (BTHB) domain, and its binding to YY1, which also binds c-‐Myc, is described. By investigating the structural and dynamic properties of c-‐Myc and c-‐Myc-‐interacting proteins, this thesis thus provides further insight to the molecular basis for c-‐Myc functionality in transcriptional regulation.
|
|
| 11. |
- Larsson, Elin, 1996, et al.
(författare)
-
Establishment of the Patient Acceptable Symptom State (PASS) for the Achilles Tendon Total Rupture Score in a Swedish Population
- 2024
-
Ingår i: ORTHOPAEDIC JOURNAL OF SPORTS MEDICINE. - 2325-9671. ; 12:7
-
Tidskriftsartikel (refereegranskat)abstract
- Background: As the use of patient-reported outcome measures (PROMs) is increasing in orthopaedic research, there is also a growing need for a standardized interpretation of these scores, such as the Patient Acceptable Symptom State (PASS), defined as the value beyond which patients consider themselves well. The Achilles tendon Total Rupture Score (ATRS) is the only PROM specific for Achilles tendon ruptures.Purpose: To establish the PASS for the ATRS in a Swedish population.Study Design: Cross-sectional study; Level of evidence, 3.Methods: Patients treated for an acute Achilles tendon rupture at a single institution in Sweden (injured between July 1, 2018, and December 31, 2020) were asked to participate in this study. The patients completed a questionnaire consisting of the ATRS and an anchor question: "How satisfied are you with the result of your treatment?" Receiver operating characteristic curve analysis was performed to calculate the PASS threshold for a positive response to the anchor question.Results: Of 516 eligible patients, 316 (61%) were included. The time from injury to completion of the questionnaire ranged from 12 to 27 months. The PASS threshold for the ATRS was found to be 75. The median ATRS of all patients was 80; 66% of patients reached an ATRS >= 75. Overall, 79% of patients were satisfied with the results of their treatment.Conclusion: The estimated PASS for the ATRS was 75 in the general Swedish population at 12 to 27 months after an acute Achilles tendon rupture.
|
|
| 12. |
- Niklasson, Markus, et al.
(författare)
-
Robust and convenient analysis of protein thermal and chemical stability
- 2015
-
Ingår i: Protein Science. - : WILEY-BLACKWELL. - 0961-8368 .- 1469-896X. ; 24:12, s. 2055-2062
-
Tidskriftsartikel (refereegranskat)abstract
- We present the software CDpal that is used to analyze thermal and chemical denaturation data to obtain information on protein stability. The software uses standard assumptions and equations applied to two-state and various types of three-state denaturation models in order to determine thermodynamic parameters. It can analyze denaturation monitored by both circular dichroism and fluorescence spectroscopy and is extremely flexible in terms of input format. Furthermore, it is intuitive and easy to use because of the graphical user interface and extensive documentation. As illustrated by the examples herein, CDpal should be a valuable tool for analysis of protein stability.
|
|
| 13. |
- Petersson, Nils F, et al.
(författare)
-
A Master of Ergonomics Programme in Sweden
- 1997
-
Ingår i: Contents of Ergonomics, Labour Protection and Work Safety Educational Programs, Poznan 1997. ; , s. 225-231
-
Konferensbidrag (refereegranskat)abstract
- A new master programme in ergonomics is being developed by the Swedish National Institute for Working life in co-operation with the Institutes of Technology in Linköping and Lund. The course runs at ‘half-speed’ and with extensive use of IT. The course takes advantage of the students’ different professional backgrounds.
|
|
| 14. |
- Ping Heidi Iu, Yan, et al.
(författare)
-
One amino acid makes a difference-Characterization of a new TPMT allele and the influence of SAM on TPMT stability
- 2017
-
Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Thiopurine induced toxicity is associated with defects in the thiopurine methyltransferase (TPMT) gene. TPMT is a polymorphic enzyme, with most of the single nucleotide polymorphisms (SNPs) causing an amino acid change, altering the enzymatic activity of the TPMT protein. In this study, we characterize a novel patient allele c.719A amp;gt; C, named TPMT*41, together with the more common variant *3C c.719A amp;gt; G, resulting in an amino acid shift at tyrosine 240 to serine, p.Y240S and cysteine, p.Y240C respectively. We show that the patient heterozygote for c.719A amp;gt; C has intermediate enzymatic activity in red blood cells. Furthermore, in vitro studies, using recombinant protein, show that TPMT p.Y240S is less stable than both TPMTwt and TPMT p.Y240C. The addition of SAM increases the stability and, in agreement with Isothermal Titration Calorimetry (ITC) data, higher molar excess of SAM is needed in order to stabilize TPMT p.Y240C and TPMT p.Y240S compared to TPMTwt. Molecular dynamics simulations show that the loss of interactions is most severe for Y240S, which agrees with the thermal stability of the mutations. In conclusion, our study shows that SAM increases the stability of TPMT and that changing only one amino acid can have a dramatic effect on TPMT stability and activity.
|
|
| 15. |
- Saellström Bonnevier, Sara, et al.
(författare)
-
Magisterutbildning i Ergonomi
- 1998
-
Ingår i: Proceedings NES'98 Nordiska Ergonomisällskapets årskonferens. ; , s. 51-53
-
Konferensbidrag (refereegranskat)
|
|
| 16. |
|
|
| 17. |
- Tu, William B., et al.
(författare)
-
Myc and its interactors take shape
- 2015
-
Ingår i: Biochimica et Biophysica Acta. Gene Regulatory Mechanisms. - : Elsevier. - 1874-9399 .- 1876-4320. ; 1849:5, s. 469-483
-
Forskningsöversikt (refereegranskat)abstract
- The Myc oncoprotein is a key contributor to the development of many human cancers. As such, understanding its molecular activities and biological functions has been a field of active research since its discovery more than three decades ago. Genome-wide studies have revealed Myc to be a global regulator of gene expression. The identification of its DNA-binding partner protein, Max, launched an area of extensive research into both the protein-protein interactions and protein structure of Myc. In this review, we highlight key insights with respect to Myc interactors and protein structure that contribute to the understanding of Mycs roles in transcriptional regulation and cancer. Structural analyses of Myc show many critical regions with transient structures that mediate protein interactions and biological functions. Interactors, such as Max, TRRAP, and PTEF-b, provide mechanistic insight into Mycs transcriptional activities, while others, such as ubiquitin ligases, regulate the Myc protein itself. It is appreciated that Myc possesses a large interactome, yet the functional relevance of many interactors remains unknown. Here, we discuss future research trends that embrace advances in genome-wide and proteome-wide approaches to systematically elucidate mechanisms of Myc action. This article is part of a Special Issue entitled: Myc proteins in cell biology and pathology. (C) 2014 Elsevier B.V. All rights reserved.
|
|
| 18. |
- Wei, Yong, et al.
(författare)
-
Multiple direct interactions of TBP with the MYC oncoprotein
- 2019
-
Ingår i: Nature Structural & Molecular Biology. - : NATURE PUBLISHING GROUP. - 1545-9993 .- 1545-9985. ; 26:11, s. 1035-
-
Tidskriftsartikel (refereegranskat)abstract
- Transcription factor c-MYC is a potent oncoprotein; however, the mechanism of transcriptional regulation via MYC-protein interactions remains poorly understood. The TATA-binding protein (TBP) is an essential component of the transcription initiation complex TFIID and is required for gene expression. We identify two discrete regions mediating MYC-TBP interactions using structural, biochemical and cellular approaches. A 2.4 -angstrom resolution crystal structure reveals that human MYC amino acids 98-111 interact with TBP in the presence of the amino-terminal domain 1 of TBP-associated factor 1 (TAF1(TAND1)). Using biochemical approaches, we have shown that MYC amino acids 115-124 also interact with TBP independently of TAF1(TAND1). Modeling reveals that this region of MYC resembles a TBP anchor motif found in factors that regulate TBP promoter loading. Site-specific MYC mutants that abrogate MYC-TBP interaction compromise MYC activity. We propose that MYC-TBP interactions propagate transcription by modulating the energetic landscape of transcription initiation complex assembly.
|
|
| 19. |
- Zimdahl, Anna, 1987-, et al.
(författare)
-
Pharmacogenetic studies of thiopurine methyltransferase genotype-phenotype concordance and effect of methotrexate on thiopurine metabolism
- 2021
-
Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley-Blackwell Publishing Inc.. - 1742-7835 .- 1742-7843. ; 128:1, s. 52-65
-
Forskningsöversikt (refereegranskat)abstract
- The discovery and implementation of thiopurine methyltransferase (TPMT) pharmacogenetics has been a success story and has reduced the suffering from serious adverse reactions during thiopurine treatment of childhood leukaemia and inflammatory bowel disease. This MiniReview summarizes four studies included in Dr Zimdahl Kahlin's doctoral thesis as well as the current knowledge on this field of research. The genotype-phenotype concordance of TPMT in a cohort of 12 663 individuals with clinically analysed TPMT status is described. Notwithstanding the high concordance, the benefits of combined genotyping and phenotyping for TPMT status determination are discussed. The results from the large cohort also demonstrate that the factors of gender and age affect TPMT enzyme activity. In addition, characterization of four previously undescribed TPMT alleles (TPMT*41, TPMT*42, TPMT*43 and TPMT*44) shows that a defective TPMT enzyme could be caused by several different mechanisms. Moreover, the folate analogue methotrexate (MTX), used in combination with thiopurines during maintenance therapy of childhood leukaemia, affects the metabolism of thiopurines and interacts with TPMT, not only by binding and inhibiting the enzyme activity but also by regulation of its gene expression.
|
|
| 20. |
- Zimdahl Kahlin, Anna, et al.
(författare)
-
Comprehensive study of thiopurine methyltransferase genotype, phenotype, and genotype-phenotype discrepancies in Sweden
- 2019
-
Ingår i: Biochemical Pharmacology. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0006-2952 .- 1356-1839. ; 164, s. 263-272
-
Tidskriftsartikel (refereegranskat)abstract
- Thiopurines are widely used in the treatment of leukemia and inflammatory bowel diseases. Thiopurine metabolism varies among individuals because of differences in the polymorphic enzyme thiopurine methyltransferase (TPMT, EC 2.1.1.67), and to avoid severe adverse reactions caused by incorrect dosing it is recommended that the patients TPMT status be determined before the start of thiopurine treatment. This study describes the concordance between genotyping for common TPMT alleles and phenotyping in a Swedish cohort of 12,663 patients sampled before or during thiopurine treatment. The concordance between TPMT genotype and enzyme activity was 94.5%. Compared to the genotype, the first measurement of TPMT enzyme activity was lower than expected for 4.6% of the patients. Sequencing of all coding regions of the TPMT gene in genotype/phenotype discrepant individuals led to the identification of rare and novel TPMT alleles. Fifteen individuals (0.1%) with rare or novel genotypes were identified, and three TPMT alleles (TPMT*42, *43, and *44) are characterized here for the first time. These 15 patients would not have been detected as carrying a deviating TPMT genotype if only genotyping of the most common TPMT variants had been performed. This study highlights the benefit of combining TPMT genotype and phenotype determination in routine testing. More accurate dose recommendations can be made, which might decrease the number of adverse reactions and treatment failures during thiopurine treatment.
|
|
