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Intron Retention: A Common Splicing Event within the Human Kallikrein Gene Family

¹ Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
² Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
³ Discipline of Pathology, Memorial University, St. John’s, NL, Canada.
⁴ Urology, University Hospital Charité, Humboldt University, Berlin, Germany.

^aAddress correspondence to this author at: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Ave., Toronto, ON, Canada M5G 1X5. Fax 416-586-8628; e-mail ediamandis{at}mtsinai.on.ca.

Background: All human kallikrein (KLK) genes have at least one splice variant, some of which possess clinical utility in cancer diagnostics/prognostics. Given that introns <100 bp in length are retained in 95% of human genes and that splice variants of KLK3 and KLK4 retain intron III, we hypothesized that other proteins in this family, with a small intron III, may also retain it.

Methods: Variant-specific reverse transcription-PCRs (RT-PCRs) for KLK1, KLK2, KLK5, and KLK15 were used to identify and clone the full coding sequence of intron III-containing splice variants. In addition, variant-specific RT-PCRs for the cloned KLK3 and KLK4 variants as well as for the "classical" forms of the six genes were used to determine their expression profiles in healthy tissues, their regulation by steroids, and their differential expression in prostate cancer.

Results: KLK1, KLK2, KLK3, KLK4, KLK5, and KLK15 showed a common type of splice variant in which intron III is retained. Expression profiling of these splice variants revealed expression profiles similar to those of the classical mRNA forms, although the pattern of hormonal regulation was different. The KLK15 splice variant was up-regulated in 8 of 12 cancerous prostate tissues. All encoded variant proteins were predicted to be truncated and catalytically inactive because of a lack of the serine residue of the catalytic triad.

Conclusions: The first six centromeric members of the KLK gene family have splice variants that retain intron III. Some variants show tissue-specific expression. The KLK15 splice variant appears to be a candidate biomarker for prostate cancer.

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				J. L.V. Shaw and E. P. Diamandis Distribution of 15 Human Kallikreins in Tissues and Biological Fluids Clin. Chem., August 1, 2007; 53(8): 1423 - 1432. [Abstract] [Full Text] [PDF]

				L. Holzscheiter, J. C. Biermann, M. Kotzsch, P. Prezas, J. Farthmann, G. Baretton, T. Luther, V. C.G. Tjan-Heijnen, M. Talieri, M. Schmitt, et al. Quantitative Reverse Transcription-PCR Assay for Detection of mRNA Encoding Full-Length Human Tissue Kallikrein 7: Prognostic Relevance of KLK7 mRNA Expression in Breast Cancer Clin. Chem., June 1, 2006; 52(6): 1070 - 1079. [Abstract] [Full Text] [PDF]