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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-09-0038v1 JOE-09-0038v2 201/3/387    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hahn, M. A. Articles by Marsh, D. J. Search for Related Content PubMed PubMed Citation Articles by Hahn, M. A. Articles by Marsh, D. J.

M Hahn, Hormones and Cancer, Kolling Institute of Medical Research, St Leonards, Australia
J McDonnell, Hormones and Cancer, Kolling Institute of Medical Research, St Leonards, Australia
D Marsh, Hormones and Cancer, Kolling Institute of Medical Research, St Leonards, 2065, Australia

Correspondence: Deborah Joy Marsh, Email: dmarsh{at}med.usyd.edu.au

Mutations in the tumour suppressor HRPT2 occur in patients with parathyroid carcinoma, kidney tumours and Hyperparathyroidism Jaw Tumour Syndrome. Disruption of exonic splicing through mutation of donor/acceptor splice sites or exonic splice enhancer (ESE) sites leads to loss-of-function of a number of major tumour suppressors including BRCA1, APC and MLH1. Given that the effect of HRPT2 mutations on splicing has not been widely studied, we used an in vitro splicing assay to determine whether 17 HRPT2 mutations located in hot-spot and other exons predicted to disrupt ESE consensus sites led to aberrant splicing. Using two independent web-based prediction programs, the majority of these mutations were predicted to disrupt ESE consensus sites, however aberrant splicing of HRPT2 transcripts was not observed. Canonical donor or acceptor splice site mutations were also investigated using this splicing assay and transcripts assessed from tumour tissue. Splice site mutations were shown to lead to either exon skipping or retention of intronic sequences through the use of cryptic splice sites comprised of non-classical splicing signals. Aberrant splicing caused by disruption of ESE sites does not appear to have a major role in HRPT2-associated disease, however premature truncation of parafibromin as the result of canonical donor or acceptor splice site mutations is associated with pathogenicity. Functional splicing assays must be undertaken in order to confirm web-based software predictions of the modification of putative ESE sites by disease associated mutations.