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 (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.
Original language | English |
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Pages (from-to) | 1955-63 |
Number of pages | 9 |
Journal | Human molecular genetics |
Volume | 14 |
Issue number | 14 |
DOIs | |
Publication status | Published - 15 Jul 2005 |
Externally published | Yes |
Keywords
- Animals
- Blotting, Southern
- Cell Line
- Cell Polarity
- Chromosomes, Human, Pair 12
- Chromosomes, Human, Pair 15
- Cricetinae
- Cysteine Endopeptidases
- DNA Primers
- Endopeptidases/genetics
- Humans
- In Situ Hybridization, Fluorescence
- Molecular Chaperones/genetics
- Reverse Transcriptase Polymerase Chain Reaction
- Subcellular Fractions/metabolism
- Teratoma/genetics
- Translocation, Genetic