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Human Molecular Genetics Advance Access published online on May 25, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi200
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received February 4, 2005
Revised April 10, 2005
Accepted May 17, 2005

Article

Fusion of the SUMO/Sentrin-specific protease 1 gene SENP1 and the embryonic polarity-related mesoderm development gene MESDC2 in a patient with an infantile teratoma and a constitutional t(12;15)(q13;q25)

Imke M. Veltman 1, Lilian A. Vreede 1, Jinke Cheng 2, Leendert H.J. Looijenga 3, Bert Janssen 1, Eric F.P.M. Schoenmakers 1, Edward T.H. Yeh 2, and Ad Geurts van Kessel 1*

1 Department of Human Genetics, Radboud University Nijmegen Medical Centre , P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
2 Department of Cardiology, Unit 449, University of Texas-MD Anderson Cancer Center, 1515 Holcombe Blvd. Houston, TX 77030, USA
3 Department of Pathology, Erasmus Medical Center/Daniel den Hoed, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands

* To whom correspondence should be addressed.
Ad Geurts van Kessel, E-mail: a.geurtsvankessel{at}antrg.umcn.nl


  Abstract

Recently we identified a patient with an infantile sacrococcygeal teratoma and a constitutional t(12;15)(q13;q25). Here we show that, as a result of this chromosomal translocation, the SUMO/Sentrin-specific protease 1 gene SENP1 on chromosome 12 and the embryonic polarity-related mesoderm development gene MESDC2 on chromosome 15 are disrupted and fused. Both reciprocal SENP1-MESDC2 (SEME) and MESDC2-SENP1 (MESE) fusion genes are transcribed in tumor-derived cells and their open reading frames encode aberrant proteins. As a consequence of this, and in contrast to wild-type MESDC2, the translocation associated SEME protein is no longer targeted to the endoplasmatic reticulum, leading to a presumed loss of function as a chaperone for the WNT co-receptors LRP5 and/or LRP6. Ultimately, this might lead to abnormal development and/or routing of germ cell tumor precursor cells. SUMO, a post-translational modifier plays an important role in several cellular key processes and is cleaved from its substrates by wild-type SENP1. Using a PML desumoylation assay we found that translocation-associated MESE proteins exhibit desumoylation capacities similar to those observed for wild-type SENP1. We speculate that spatio-temporal disturbances in desumoylating activities during critical stages of embryonic development might have predisposed the patient. Together, the constitutional t(12;15)(q13;q25) translocation revealed two novel candidate genes for neonatal/infantile GCT development: MESDC2 and SENP1.


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