Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2021
Erindi/veggspjald / Talk/poster E27
Höfundar / Authors: Hilmar Örn Gunnlaugsson (1), Sara Þöll Halldórsdóttir (1), Ellen Dagmar Björnsdóttir (1), Teresa Luperchio (4), Hans Tómas Björnsson (1-4)
Starfsvettvangur / Affiliations: 1. Department of Biochemistry and Molecular Biology, Biomedical Center, Faculty of Medicine, University of Iceland, Reykjavík, Iceland, 2. Faculty of Medicine, University of Iceland, Reykjavík, Iceland, 3. Faculty of Genetics and Molecular Medicine, Landspítali University Hospital, Reykjavík, Iceland, 4. McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Kynnir / Presenter: Hilmar Örn Gunnlaugsson
Kabuki syndrome (KS) is a rare Mendelian disorder of the epigenetic machinery (MDEM) which commonly occurs due to variants in KMT2D, a histone methyltransferase known to methylate H3K4. Previously, researchers have developed loss of function mouse models for KS displaying overlapping features to individuals with KS including postnatal growth retardation and IgA-deficiency but also novel phenotypes such as defects in formation of Peyer´s patches, adult neurogenesis, and hippocampal memory. A subset of individuals with KS have missense variants and these appear to pinpoint specific domains that are critical to the disease. To model this situation, we have used CRISPR-Cas9 to introduce a patient specific missense variant (p.R5179H) into C57BL/6J mice (Kmt2d+/R5230H). This will allow us for the first time to characterize a patient specific mouse model for KS and will allow us a more clinically significant model for the disorder. These mice have already shown similar phenotypes to KS patients such as postnatal growth retardation (P<0.001) and fewer Peyer’s patches in the small intestine (P<0.01). These mice have also shown renal abnormalities for the first time which are also found in individuals with KS. We are testing the mice for both reduced adult neurogenesis in the dentate gyrus as well as for hippocampal memory and IgA defects. We are also knocking in the patient specific variant into commercial cell lines for further validation of the mechanistic basis of this variant.