Schinzel-Giedion syndrome (SGS, MIM#269150) is caused by heterozygous de novo mutations in the SETBP1 gene. This gene provides instructions for making a protein called SET binding protein 1. This protein binds the SET nuclear oncogene, involved in DNA replication. The gene is shown to be expressed in numerous tissues and multiple transcript variants encoding different isoforms have been found. The function of this protein is still largely unknown. In SGS, missense mutations cluster in a small region (the hotspot region) of the gene in exon 4 leading to a gain of function. Different mutations within and around the SETBP1 hotspot have been shown to have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Normally, proteins such as SETBP1 are degraded some time after formation. Due to a hotspot mutation in SETBP1, the protein is changed in such a way that the cell’s degradation machinery cannot not bind to the protein efficiently. Therefore less protein will be degraded and a sort of overproduction of SETBP1 protein will develop. How this then leads to SGS is still unknown and further research is necessary to learn more about SETBP1 dysfunction and how this leads to SGS. Identical SETBP1 hotspot mutations have recurrently been observed as somatic events in leukemia.
Diagnostic testing is performed by sequence analysis of the entire coding region.