Multi-forms of human MTH1 polypeptides produced by alternative translationinitiation and single nucleotide polymorphism

The human MTH1 gene for 8-oxo-7,8-dihydrodeoxyguanosine triphosphatase, pro duces seven types (types 1, 2A, 2B, 3A, 3B, 4A and 4B) of mRNAs, The B-type mRNAs with exon 2b-2c segments have three additional in-frame AUGs in thei r 5' regions. We report here that these transcripts produce three forms of MTH1 polypeptides(p22, p21 and p18) in in vitro translation reactions. Thre e polypeptides were also detected in extracts of human cells, using western blotting. B-type mRNAs with a polymorphic alteration (GU->GC) at the begin ning of exon 2c that converts an inframe UGA to CGA yielding another in-fra me AUG further upstream, produced an additional polypeptide (p26) in vitro. Substitution of each AUG abolished the production of each corresponding po lypeptide. Cell lines from individuals with the GC allele contain more B-ty pe mRNAs than do those of GT homozygotes, and the former produce all of fou r polypeptides but the latter lack p26, Amounts of each polypeptide reflect ed copy number of the GC allele in each cell line. There is an apparent lin kage disequilibrium between the two polymorphic sites, GT/GC at exon 2c and Val83/Met83 at codon 83 for p18.