A novel mouse and neuronal model to mechanistically test hypothesis in Kabuki syndrome

Main author: Hilmar Örn Gunnlaugsson
Institution or Company: University of Iceland

Co-Authors, Institution or Company:
Ellen Dagmar Björnsdóttir¹, Sara Þöll Halldórsdóttir¹, Teresa Luperchio⁴, Hans Tómas Björnsson^1-4

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

Introduction: Kabuki syndrome (KS) is a rare Mendelian disorder of the epigenetic machinery (MDEM) most commonly caused by de novo loss of function mutations in KMT2D, this gene encodes a transcriptional activator that adds histone methylation to H3K4. The symptoms of KS include intellectual disability, postnatal growth retardation, and craniofacial abnormalities. Previously, researchers have demonstrated an ongoing defect of adult neurogenesis and hippocampal memory defects in a mouse model of KS. However, previous mouse models have been artificial, and we have not had a neuronal model that would allow functional validation of mechanistic hypotheses.

Methods: We have used CRISPR-Cas9 to insert a KMT2D mutation found in a patient (p.R5179H) into C57BL/6J mice (Kmt2d^+/R5230H) to generate a more clinically relevant mouse model for KS. We will validate previously observed phenotypes (behavioral testing, quantification of adult neurogenesis) in Kmt2d^+/R5230H mice. We will isolate primary neuronal progenitor cells (NPCs) from E18.5 embryonic brain tissue to test mechanistic hypotheses using these cells.

Results: Kmt2d^+/R5230H mice have similar phenotypes to KS patients and previous mouse models such as postnatal growth retardation (P<0.001) and reduced Peyer’s patches in the small intestine (P<0.01). These mice also have other observed phenotypes including kidney and olfactory abnormalities. We have successfully isolated NPCs and have shown increased proliferation rate and abnormal metabolic states. The NPCs also demonstrate differential gene expression patterns.

Conclusion: Kmt2d^+/R5230H is the first patient specific model for Kabuki syndrome, and it is our hope that our NPC neuronal model will show cellular phenotypes that allow us to test various mechanistic hypotheses.

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