Detection of a Novel Single Nucleotide Polymorphism of the Human Thiopurine S-Methyltransferase Gene in a Chinese Individual

Abstract

A 62-year-old Chinese patient with recurrent pompholyx submitted his blood sample for pre-treatment thiopurine S-methyltransferase (TPMT) pharmacogenetic profiling, and it was found to harbour a novel single nucleotide polymorphism (SNP). The novel SNP, detected by mRNA sequencing, was a c.2T>C (g.11018T>C) transition in the start codon, causing a Met1Thr amino acid change. This finding was confirmed on a subsequent blood sample from the same patient by DNA sequencing. The patient was genotyped as TPMT*1/*29, sequentially named as such following the latest TPMT SNP (TPMT*1/*28) at the time of writing. The novel SNP is expected to result in complete lack of protein translation, similar to the impact exerted by TPMT*14, another start codon SNP of the TPMT gene.

Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease

“…The allele for normal TPMT activity (wildtype) has been designated TPMT*1. To date, 31 different variant TPMT alleles (TPMT*2‐TPMT*29) have been reported, and are associated with decreased enzyme activity, compared with the wild allele . However, previously described mutations affecting coding sequences of the TPMT gene are not sufficient to explain the large variability in enzymatic activity observed in the general population.…”

High-Resolution Melting Analysis of theTPMTGene: A Study in the Polish Population

“…Moreover, the other two substitution, which so far remained unknown, were identified: in exon 3 c.200T > C (p.Phe67Ser) and in exon 8 c.595G > A (p.Val199Ile). These 2 novel TPMT variants were named TPMT*30 and *31, following to the last-described TPMT*29 allele (Lee et al, 2012). Both changes are located in the conservative region of the TPMT gene (Salavaggione et al, 2005) and cause the amino acid exchange, which indicates possible influence on lowered enzyme activity and is a subject for further investigation.…”

“…Approximately 1 in 300 persons (0.3%) has low or undetectable TPMT enzyme activity, whereas about 11% are heterozygous for TPMT gene mutations resulting in intermediate TPMT activity (Weinshilboum, 2001). There are currently 31 known alleles responsible for TPMT deficiency (TPMT*2, *3A, *3B, *3C, *3D, *4, *5, *6, *7, *8, *9, *10, *11, *12, *13, *14, *15, *16, *17, *18, *19, *20, *21, *22, *23, *24, *25, *26, *27, *28, and *29) and 3 alleles associated with normal TPMT activity (TPMT*1 and two silent polymorphisms) (Derijks and Wong, 2010;Lee et al, 2012). The TPMT*2 (c.238G > C), *3A (c.460G > A, c.719A > G), and *3C (c.719A > G) alleles account for 80% to 95% of inherited TPMT deficiency in different populations all over the world (Yates et al, 1997).…”

Pharmacogenetic studies of thiopurine methyltransferase genotype-phenotype concordance and effect of methotrexate on thiopurine metabolism

“…The cDNA which corresponds to TPMT mRNA exons 3-8 or exons 5-10 was amplified using PCR and primers hybridizing over the exon-boundaries to exclude contaminating gDNA and the TPMT pseudogene [107].…”