Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.67 (thiopurine methyltransferase)
 551 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thiopurines (azathioprine and mercaptopurine) are widely used in patients with inflammatory bowel disease. In this paper, we review the main indications for their use, as well as practical aspects on efficacy, safety and method of administration. They are mainly used to maintain remission in steroid-dependent disease or with ciclosporin to control a severe ulcerative colitis flare-up, as well as to prevent postoperative Crohn's disease recurrence, and also in combination therapy with biologics. About 30-40% of patients will not respond to treatment and 10-20% will not tolerate it due to adverse effects. Before they are prescribed, immunisation status against certain infections should be checked. Determination of thiopurine methyltransferase activity (TPMT) is not mandatory but it increases initial safety. The appropriate dose is 2.5mg/kg/day for azathioprine and 1.5mg/kg/day for mercaptopurine. Some adverse effects are idiosyncratic (digestive intolerance, pancreatitis, fever, arthromyalgia, rash and some forms of hepatotoxicity). Others are dose-dependent (myelotoxicity and other types of hepatotoxicity), and their surveillance should never be interrupted during treatment. If therapy fails or adverse effects develop, management can include switching from one thiopurine to the other, reducing the dose, combining low doses of azathioprine with allopurinol and assessing metabolites, before their use is ruled out. Non-melanoma skin cancer, lymphomas and urinary tract tumours have been linked to thiopurine therapy. Thiopurine use is safe during conception, pregnancy and breastfeeding.
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PMID:Recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) on the use of thiopurines in inflammatory bowel disease. 2935 99

Determining the pathogenicity of genetic variants is a critical challenge, and functional assessment is often the only option. Experimentally characterizing millions of possible missense variants in thousands of clinically important genes requires generalizable, scalable assays. We describe variant abundance by massively parallel sequencing (VAMP-seq), which measures the effects of thousands of missense variants of a protein on intracellular abundance simultaneously. We apply VAMP-seq to quantify the abundance of 7,801 single-amino-acid variants of PTEN and TPMT, proteins in which functional variants are clinically actionable. We identify 1,138 PTEN and 777 TPMT variants that result in low protein abundance, and may be pathogenic or alter drug metabolism, respectively. We observe selection for low-abundance PTEN variants in cancer, and show that p.Pro38Ser, which accounts for ~10% of PTEN missense variants in melanoma, functions via a dominant-negative mechanism. Finally, we demonstrate that VAMP-seq is applicable to other genes, highlighting its generalizability.
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PMID:Multiplex assessment of protein variant abundance by massively parallel sequencing. 2978 12