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).
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.
Veltman
Imke M
IM
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Vreede
Lilian A
LA
Cheng
Jinke
J
Looijenga
Leendert H J
LH
Janssen
Bert
B
Schoenmakers
Eric F P M
EF
Yeh
Edward T H
ET
van Kessel
Ad Geurts
AG
D000818:Animals; D015139:Blotting, Southern; D002460:Cell Line; D016764:Cell Polarity; D002881:Chromosomes, Human, Pair 12; D002884:Chromosomes, Human, Pair 15; D006224:Cricetinae; D003546:Cysteine Endopeptidases; D017931:DNA Primers; D010450:Endopeptidases / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D018832:Molecular Chaperones / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000378:metabolism; D013724:Teratoma / Q000235:genetics*; D014178:Translocation, Genetic
D017931:DNA Primers; C506348:MESD protein, human; D018832:Molecular Chaperones; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases