Main author: Tinna Reynisdóttir
Institution or Company: University Of Iceland
Co-Authors, Institution or Company:
Hans Tómas Björnsson, Landspítali, Johns Hopkins University. Hilmar Örn Gunnlaugsson, University Of Iceland.
Introduction: Wiedemann-Steiner syndrome (WSS) is a Mendelian disorder of the epigenetic machinery (MDEM) caused by heterozygous disease-causing variants in the KMT2A gene. WSS is characterized by intellectual disability, growth retardation and hypertrichosis. Three other MDEMs (Rett, kabuki and Rubinstein-Taybi syndromes) show postnatal rescue of the neurological phenotype and here we want to ask whether WSS is another treatable cause of intellectual disability.
Methods: In collaboration with the Jackson laboratory, we have created a mouse model using CRISPR-Cas9. These mice (Kmt2a+/-(LSL)) carry a loss of function variant in intron 2 of the gene surrounded by loxP sites. This allows us to remove the loss of function variant by exposure to Cre. We will perform detailed phenotyping of Kmt2a+/-(LSL) mice to seek robust pre-clinical outcome measures and breed them to an inducible Cre line, which releases Cre upon exposure to Tamoxifen (TM). Using this cross, we can test whether postnatal administration of TM can rescue KMT2A levels and other outcome measures in adult animals.
Results: Kmt2a+/-(LSL) mice demonstrate decreased Mendelian ratios of the LSL allele indicating functionality of the allele. We have created two independent lines to be able to demonstrate that any results don’t relate to CRISPR off target sites. The mice will be shipped from the Jacksons laboratory in March 2021.
Conclusion: If this research project is successful, it will lead to a new fully characterized WSS mouse model for the international research community and demonstrate robustly that there is postnatal malleability in WSS.
