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(Vienna, July 6, 2018) In order to absorb the fats from our diet, we must undergo a series of chains of complex biochemical reactions. The fat molecules, consisting of a glycerol and three fatty acids (also called triglycerides), must first be broken down into their constituents to be absorbed by the cells of the intestinal mucosa. In these cells, triglycerides are restored and packaged in small transport particles that are released into the bloodstream. If it comes in these processes of fat digestion to disturbances, which can have devastating effects.
This has been demonstrated in ten children from six families who have suffered from CDD since birth and therefore severe diarrhea and / or vomiting. After a series of ineffective conventional therapies, Kaan Boztug, Director of the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) and Associate Research Group Leader of the CeMM Molecular Medicine Research Center at Austrian Academy of Sciences. In collaboration with the Medical University of Innsbruck, the Utrecht University Medical Center and the School of Medicine of Ankara University, the researchers carried out the sequencing of DNA with the patient's genome and identified mutations in the gene for diacylglycerol acyltransferase 1 (DGAT1) protein. The study was published in the journal Gastroentorology. (DOI: 10.1053 / j.gastro.2018.03.040)
DGAT1 is an enzyme responsible for the final step of triglyceride formation in intestinal mucosal cells. The researchers were able to show that mutations in the DGAT1 gene found in patients resulted in reduced or completely arrested protein production in the cells. Other experiments have shown that these cells were unable to properly use fats for their metabolism. In addition, researchers were able to grow intestinal organoids – miniaturized and simplified structures with organ-like properties – from patient biopsies and monitor the effects of the genetic defect.
"Intestinal organoids are excellent model systems for studying gastrointestinal diseases," says Rico Ardy, a PhD student at LBI-RUD and co-lead author of the study. "With other experimental approaches, they have allowed us to elucidate the genetic cause and molecular mechanisms of this rare disease.In general, our results show the role of DGAT1 in healthy lipid metabolism."
Study is further evidence that genetic badysis is an important contribution to the development of appropriate care and therapy for patients with conbad diseases. The article also highlights the general importance of research on rare diseases that in many cases not only helps patients, but also provides new insights into human biology. "Research on rare diseases often reveals fundamental processes in human physiology and helps us find therapies in cases where conventional approaches fail," adds Kaan Boztug. "Patients with DGAT1 deficiency were initially on a fat-free diet. which normalized their digestion. Meanwhile, LBI-RUD researchers are working on more specific and personalized therapies to target such genetic diseases in the future. "
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The study" Intestinal Impairment and Aberrant Lipid Metabolism in Patients with DGAT1 Deficiency "Gastroenterology Review, July 2018. DOI: 10.1053 / j.astro.2018.03.040 [19659002] Authors: Jorik M van Rijn #, Rico Chandra Ardy #, Zarife Kuloğlu #, Bettina Hardener #, Désirée Y. Van Haaften-Visser # Hubert van der Doef, Marliek van Hoesel, Aydan Kansu, Anke HM van Vugt, Marini Thian , Freddy TM Kokke, Ana Krolo, Meryem Keçeli Başaran, Neslihan Gürcan Kaya, Aysel Ünlüsoy Aksu, Buket Dalgıç, Figen Ozcay, Zeren Baris, Renate Kain, Edwin C. Stigter, Klaske D Lichtenbelt, Maarten PG Mbadink, Karen Duran J, BGM Verheij, Dorien Lugtenberg, Peter GJ Nikkels, Henricus GF Brouwer, Henkjan Verkade, René Scheenstra, Bart Spee, Edward ES Nieuwenhuis, Paul J. Coffer, Andreas R Janecke, Gijs van Haaften, Roderick HJ Houwen, Thomas Müller *, Sabine Middendorp * and Kaan Boztug * (# Co-first authors, * last co-authored
Funding: This study was funded by the Austrian Academy of Sciences, the Jubilee Fund OENB, the Netherlands Organization for Scientific Research. Kaan Boztug studied medicine in Düsseldorf, Friborg and London before completing his doctorate under Iain Campell at Scripps Research Institute (La Jolla, USA). He completed his clinical and postdoctoral training with Christoph Klein at Hannover Medical School. In 2011, he accepted a group leader position at CeMM and is an badociate professor in the pediatric department of the Medical University of Vienna. He is Director of the Vienna CeRUD Center for Rare and Undiagnosed Diseases and Director of the Jeffrey Model Diagnostic and Research Center in Vienna at the St. Anna Children's Hospital and the Vienna Medical University. Kaan Boztug has since 2016 been head of the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD).
The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an international, independent and interdisciplinary research institution for molecular medicine under the scientific direction of Giulio Superti-Furga. Focused on medical needs, CeMM integrates basic research and clinical expertise to develop innovative diagnostic and therapeutic approaches in precision medicine. The research focuses on cancer, inflammation, metabolic and immune disorders as well as rare diseases. The research building of the institute is located on the campuses of the Medical University and the Vienna General Hospital. www.cemm.at
The Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) was founded by the Ludwig Boltzmann Society in April 2016 in cooperation with the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. and St. Anna's childhood cancer research. The research focus of LBI-RUD is on the decoding of rare diseases of blood formation, immune system and nervous system. This work not only serves as a foundation for the development of personalized therapeutic approaches for those directly affected, but also provides human biology. The goal of LBI-RUD is to establish a coordinated research program integrating the scientific, social, ethical and economic aspects of rare diseases, taking into account the expertise of its partner organizations.
www.lbg.ac.at
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of the Austrian Academy of Sciences
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