Sequence Variations of Human Kallikrein Genes

Sequence changes, including polymorphisms and mutations, are clinically important. in addition to medicolegal applications, they can also be indicators for susceptibility and prognosis for different malignancies [52]. KLK3 is the most extensively studied kallikrein in this respect. Comparison of the published mRNA sequences of KLK3 revealed infrequent and inconsistent sequence variations. Baffa et al. found no evidence of mutations in the KLK3 mRNA sequence in prostate cancer compared to matched normal tissues from the same patient [53]. Similarly, no mutations were found in the coding portion of the KLK3 gene in breast cancer tissues and cell lines, with the exception of a polymorphism in exon 2 in some breast tumors [54]. Three distinct forms of KLK1 mRNA, differing in one or two amino acid substitutions, were identified in different tissues [1, 55, 56]. Experimental evidence, however, indicates that the protein products of these variants have no difference in their protein activity [57]. Probably the most polymorphic sequence of KLK4 is that deposited by Hu et al. [41]. In addition to a large insertion in the 3' untranslated region, there are 18 differences between their sequence and those deposited by others. These probable polymorphisms will affect the derived amino acid product [41]. We have recently identified a germline single nucleotide variation in exon 3 of the KLK10 gene that will change the amino acid from alanine to serine. This polymorphism is less prevalent in prostate cancer patients in comparison to control subjects [58]. Also, four other polymorphisms were identified in exon 4 of the same gene.

Within a 5.8-kb promoter/enhancer region of KLK3, 16 different muta-tional hotspots (appearing more than once in nine tumors) were found in breast cancer [54]. A single nucleotide variation (G ! A) was identified at position —158 within androgen response element 1 (ARE-1). Univariate Cox regression modeling showed a 28% reduction in the risk of death in patients with homozygous G genotype compared to those with homozygous A [59].

In general, the examination of sequence variation within the 300-kb kalli-krein locus has not been performed in detail, and it is therefore possible that inactivating mutations within the coding region of kallikrein genes exist but await discovery. Kallikrein gene inactivation in human diseases would likely provide clues for the physiological functions of these diseases.

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