Höfundar:
Tinna Reynisdottir, Kimberley Jade Anderson, Hilmar Örn Gunnlaugsson, Hans Tomas Björnsson
Introduction: Wiedemann-Steiner syndrome (WDSTS) is a Mendelian disorder of the epigenetic machinery (MDEM) caused by heterozygous disease-causing variants in the KMT2A gene. WDSTS is characterized by unusual facial features, intellectual disability and growth retardation. Related MDEMs have previously been shown to demonstrate postnatal rescue of disease phenotypes. The aim of this study is to explore whether WDSTS could potentially be treatable in utero.
Methods: We have designed an innovative mouse model for WDSTS (Kmt2a+/-LSL) that carries a cassette containing a stop codon flanked by loxP sites on either side, resulting in heterozygous Kmt2a expression. Upon exposure to Cre, the cassette should theoretically be removed, restoring full Kmt2a expression. We will characterize the Kmt2a+/-LSL mice, prove that the cassette can be removed and cross them with a nestin-Cre mouse model in an effort to rescue Kmt2a expression in the nervous system during gestation. Using this cross, we can test whether in utero rescue of KMT2A-levels can rescue the WDSTS neurological phenotype.
Results: Kmt2a+/-LSL mice demonstrate WDSTS-like phenotypes, such as significant growth retardation (p<0.0001), hypotonia (surface righting p=0.0107, hindlimb suspension p=0.0401) and apparent craniofacial dysmorphism, compared to wild-type littermates. The mice demonstrate defects of hippocampal dependent memory (Y-maze, p=0.0346) and potential defects in melanoblast cell migration. Conclusion: If successful, this project will establish a valuable reagent (Kmt2a+/-LSL mice) and test whether the neurological dysfunction of WDSTS has in utero malleability, opening up the possibility of future therapeutic trials for WDSTS.