Eugene Y. Krynetski, PhD; William E. Evans, PharmD
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Krynetski E., Evans W.; Molecular Diagnosis of Thiopurine S-Methyltransferase Deficiency. Ann Intern Med. 1997;127:1041-1042. doi: 10.7326/0003-4819-127-11-199712010-00027
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Published: Ann Intern Med. 1997;127(11):1041-1042.
We are pleased by Dr. Blank's interest in our paper and offer the following in response to points raised in his letter. We have previously shown that the G238C transversion alone is associated with a 100-fold reduction in TPM catalytic activity in a heterologous expression system  and that this is the only mutation in some patients with TPM deficiency . Likewise, we have shown that the G460A and the A719G mutations are the only mutations in the TPM complementary DNA (cDNA) of other patients with TPM deficiency, and that the cDNA with only these mutations has more than a 200-fold reduction in activity in a heterologous expression system . The latter was also found by another group . We have more recently established that the proteins encoded by these two mutant alleles undergo enhanced proteolysis . Thus, alleles with these mutations are clearly associated with loss of TPM activity, based on cDNA sequencing [1-3], heterologous expression [1-4], and the concordance of phenotype and genotype.
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