title: TPMT*26 (208F-->L), a novel mutation detected in a Chinese.
abstract: OBJECTIVE
  Azathioprine, mercaptopurine and thioguanine are commonly used to treat autoimmune disorders, leukaemia and solid organ transplantation. However, azathiopurine and its metabolites can also cause adverse reactions such as myelosuppression. These manifestations may be attributed to polymorphisms or mutations in the thiopurine methyltransferase (TPMT) gene that might result in low TPMT enzyme activity. Our aim was to investigate if azathioprine-related myelosuppression is associated with TPMT polymorphism, which in turn affects its enzyme activity.
  
  
  METHODS
  A 61-year-old Chinese man with severe atopic eczema developed moderate myelosuppression with standard doses of azathioprine. His TPMT activity was measured using radiochemical assay. Genotyping of TPMT *3C, *3A and *6 were screened using polymerase chain reaction-restriction fragment length polymorphism. Novel mutation was detected by sequencing. Family studies of his three other siblings were performed.
  
  
  RESULTS
  After 4 weeks of azathioprine treatment, the patient's white blood cells and absolute neutrophil count dropped by 40-45%. He was then taken off azathioprine, and blood counts returned to normal. TPMT activity test showed intermediate levels of 9.1 nmol h(-1) ml(-1) peripheral red blood cells (pRBC). Resequencing of the TPMT gene revealed a missense mutation Phe-->Leu at 208 aa position in exon 9 (ss105107120). Two of his three siblings were heterozygous for 208F-->L, which accounts for the decreased enzyme activity (brother 8.9 nmol h(-1) ml(-1) pRBC, sister 8.8 nmol h(-1) ml(-1) pRBC). The remaining sibling had wild-type allele with normal enzyme activity. Screening of 100 normal healthy Chinese subjects did not reveal any individual with this mutation.
  
  
  CONCLUSIONS
  We report a novel mutation TPMT*26 (208F-->L) associated with a decrease in TPMT enzyme activity.
authors: Department of Paediatrics, Division of Haematology and Oncology, Yong Loo Lin School of Medicine, National University Health System, National University Hospital, 5 Lower Kent Ridge Road, Singapore.
authors: Shirley Kow Yin
authors: SK
authors: Kham
authors: Chin Kok
authors: CK
authors: Soh
authors: Derrick Chen Wee
authors: DC
authors: Aw
authors: Allen Eng Juh
authors: AE
authors: Yeoh
mesh_terms: D044466:Asian People / Q000208:ethnology / Q000235:genetics; D001379:Azathioprine / Q000009:adverse effects*; D003876:Dermatitis, Atopic / Q000188:drug therapy*; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
chemical_list: D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine