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Novel ErbB4 juxtamembrane splice variants and the truncated ErbB2 receptor isoform are frequently expressed in childhood medulloblastoma

Lookup NU author(s): Dr Richard Gilbertson, Roberto Hernan, Professor David Ellison, Emeritus Professor Robert Perry, Professor Andrew Pearson, Professor John Lunec

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Abstract

We recently reported a significant relationship between tumor cell expression of the ERBB4 receptor, the most recently described member of the epidermal growth factor receptor family, and aggressive tumor phenotype in childhood medulloblastoma. Two alternative juxtamembrane (JM) isoforms of the ERBB4 receptor have been described. Termed JMa and JMb, these variants possess different receptor processing and ligand-binding characteristics. In the current study, we employed an RT-PCR and sequencing strategy to determine the pattern of ERBB4 JM isoform expression in a large (n = 78) series of pediatric medulloblastomas. JMa and JMb transcript expression was detected in 53% and 28% of tumor samples, respectively. In addition, two novel ERBB4 JM isoforms, which we have termed JMc and JMd, were isolated from 10% and 36% of tumors, respectively. Sequence analysis revealed the JMc transcript to contain a deletion of the entire JM region. In contrast, JMd includes an extended coding region, retaining both the JMa and JMb sequences. Neither of these novel isoforms was detected in normal human adult cerebellum, but expression of JMd was observed in developing fetal cerebellum, suggesting that this later isoform may represent an ERBB4 transcript restricted to primitive neuroectoderm-derived tissue. To confirm that the four ERBB4 JM isoforms arise by alternative RNA splicing, we sequenced the intron-exon junctions of the human ERBB4 gene within the JM region. This demonstrated the four ERBB4 JM variants to be encoded by two short exons containing the JMb and JMa sequences positioned in the order 5' to 3' and separated by a 121 bp intron.


Publication metadata

Author(s): Gilbertson RJ, Hernan R, Lewin J, Pietsch T, Pinto L, Scotting P, Allibone R, Ellison D, Perry RH, Pearson ADJ, Lunec J

Publication type: Article

Publication status: Published

Journal: Genes, Chromosomes & Cancer

Year: 2001

Volume: 31

Issue: 3

Pages: 288-294

ISSN (print): 1045-2257

ISSN (electronic): 1098-2264

URL: http://dx.doi.org/10.1002/gcc.1146

DOI: 10.1002/gcc.1146

Notes: First report of tumour specific novel erbB4 receptor mRNA splice variants and erbB2 truncated isoforms in childhood medulloblastoma.


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