Málstofa Lífvísindaseturs - Kabuki heilkennið

Málstofa Lífvísindaseturs fimmtudaginn 15. nóvember kl. 12:00 í stofu 343 Læknagarði

Fyrirlesari: Dr. Hans Tómas Björnsson, yfirlæknir á erfða- og sameindalæknisfræðideild Landspitala háskólasjúkrahúss, dósent við Læknadeild Háskóla Íslands og sérfræðingur í barna- og erfðalækningum við Johns Hopkins, Bandaríkjunum.  

Titill: Kabuki syndrome: insights from studies in neurons and immune cells. 

Ágrip: The Mendelian disorders of the epigenetic machinery (MDEM) are a rapidly emerging cause of intellectual disability. These disorders occur because of heterozygous loss of function mutations in the four components of the epigenetic machinery (writer, eraser, reader and remodeler). Although, enzymes disorders tend to be recessive, three of these components (writer, eraser and remodeler) are enzymatic components but yet these disorders are overwhelmingly dominant. We have recently discovered a possible reason for the haploinsufficiency of this group. Among, 295 epigenetic machinery components we find that 74 of these factors demonstrate extensive co-expression in the publicly available GTEx dataset. Furthermore, the highly co-expressed epigenetic components are heavily enriched for genes that are extremely intolerant to variation (haploinsufficient) and associated with neurological disease. We have hypothesized that disruption of the co-expression network itself may play a mechanistic role in the pathogenesis of neurological dysfunction. We have also performed extensive studies on one of these MDEM disorders, called Kabuki syndrome. Kabuki syndrome is caused by mutations in two distinct components of the epigenetic machinery (KMT2D and KDM6A). We have characterized a novel mouse model of Kabuki syndrome type 1 (Kmt2d+/βGeo mice), but these mice have many features seen in patients with Kabuki syndrome including growth retardation, immune dysfunction and neurological dysfunction. Our group has uncovered a defect of adult neurogenesis in the granule cell layer of the hippocampus, which can be rescued by agents that favor chromatin opening. We have now created several cellular neuronal models and observe novel cellular phenotypes that appear to be consistent in multiple models (iPSC, NPC, HT22, mice). We have also performed extensive gene expression and chromatin studies to implicate some possible pathways that may explain these functional abnormalities. Similarly, our studies of the immune defect in Kabuki syndrome have revealed many abnormalities seen in patients with Kabuki syndrome but also novel disease phenotypes. Together, our studies suggest novel insights into the pathophysiology of Kabuki syndrome and open up new avenues for therapeutic development.   

Ferill: Hans Tomas Bjornsson received his medical degree from the University of Iceland. Dr. Bjornsson then received a Ph.D. degree in human genetics from the predoctoral program in genetics at Johns Hopkins, followed by combined clinical training in pediatrics and clinical genetics at Johns Hopkins. Dr. Bjornsson joined the faculty at the McKusick- Nathans Institute of Genetic Medicine and the Department of Pediatrics in 2012, where he runs a clinic dedicated to patients with imprinting disorders and Mendelian disorders of the epigenetic machinery (Epigenetic and Chromatin Clinic). His research on a mouse model of Kabuki syndrome, a Mendelian disorder of the histone machinery, has revealed that manipulation of the epigenome may be a possible therapeutic approach for the intellectual disability seen in this disorder. Since 2018 Dr. Bjornsson has been Clinical Director of Clinical Genetics at Landspitali university Hospital and Associate Professor of Translational Medicine and Pediatrics at the University of Iceland. Dr. Bjornsson has received numerous awards for both clinical care and scientific work, including the Frank Coulson, Jr. Award for Clinical Excellence (2012), an NIH director’s Early Independence Award (2013), the Sir William Osler Young Investigator Award from the Interurban Clinical Club (2014) and the William K. Bowes Jr. Award in Medical Genetics (2014).

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