Aberrant splicing of the PTPRD gene mimics microdeletions identified at this locus in neuroblastomas

Neuroblastoma (NBL), a pediatric tumor arising from precursor cells of the sympathetic nervous system, is characterized by numerous recurrent large-scale chromosomal imbalances. High resolution oligonucleotide array CGH analysis of NBL has previously identified microdeletions that are confined to the 5' UTR of the protein tyrosine phosphatase receptor D (PTPRD) gene, implicating this gene in the pathogenesis of these tumors. Here, we demonstrate that the 5' UTR of this gene, consisting of 11 noncoding exons, is also aberrantly spliced in >50% of NBL primary tumors and cell lines. The loss of exons from the 5' UTR region through aberrant splicing results in aberrant mRNA isoforms that are similar to those generated through microdeletions. The aberrant splicing or microdeletion of 5' UTR exons in such a high proportion of tumors indicates that loss of these exons dys-regulates the mRNA sequence. To further validate the role of PTPRD in NBL, we have examined the expression of this gene in normal fetal adrenal neuroblasts (the cell of origin of NBL) and in tumors from patients with either low stage or high stage disease. This gene is expressed at lower levels in high stage NBL tumors, particularly those with amplification of MYCN, relative to low stage tumors or normal fetal adrenal neuroblasts, consistent with the possibility that loss of the 5' UTR exons have destabilized the mRNA.