Journal Article

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

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

in Human Molecular Genetics

Volume 14, issue 14, pages 1955-1963
Published in print July 2005 | ISSN: 0964-6906
Published online May 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi200
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)

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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 (WT) 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 WT SENP1. Using a PML desumoylation assay, we found that translocation-associated MESE proteins exhibit desumoylation capacities similar to those observed for WT 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.

Journal Article.  6535 words.  Illustrated.

Subjects: Genetics and Genomics

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