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)

Veltman IM, Vreede LA, Cheng J, Looijenga LH, Janssen B, Schoenmakers EF, Yeh ET and van Kessel AG
Source: Hum Mol Genet
Publication Date: (2005)
Issue: 14(14): 1955-1963
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
Species: monkey
Tissue Origin: kidney
Nucleofector® I/II/2b
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