The Vogel Laboratory: Intracellular Cargo Transport in Congenital Intestinal Diseases


Our research focuses on congenital intestinal and liver diseases. Congenital intestinal disorders are often caused by mutations in genes that are essential for correct intestinal-epithelial polarisation. One example is microvillus inclusion disease. Mutations in MYO5B or STX3 were identified here; both are essential for polarised apical cargo transport of transmembrane transporters (Vogel GF et al., JCB, 2015; Vogel GF et al., JCI Insight, 2017). There is now also a new research focus on myo5b-associated cholestatic liver disease and myo5b-independent apical transport in intestinal epithelial cells.

Congenital liver disease can ultimately result in organ failure and require liver transplantation. However, the trigger and molecular mechanisms underlying liver failure remain poorly understood. We are therefore studying the contribution of endoplasmic reticulum stress and the unfolded protein response in metabolic liver diseases and associated acute liver failure. Mutations in PERK are a prominent example here, associated with Wolcott-Rallison syndrome. Liver and intestinal disease are both studied on genome-edited epithelial cell lines as well as patient-derived organoid cultures.

In a close collaboration with Andreas Janecke and Thomas Müller from Paediatrics I, we recently identified two novel missense mutations in the adaptor protein AP1S1, in patients diagnosed with congenital enteropathy. Defects in AP1S1 are associated with MEDNIK syndrome. In AP1S1 knockout CaCo2 cells, we observed altered localisation of tight-junction proteins ZO-1 and claudin 3, reduced transepithelial electrical resistance and increased dextran permeability of the CaCo2-AP1S1-KO monolayer. In addition, lumen formation in 3D cultures of these cells was abnormal. Re-expression of wild-type AP1S1 in CaCo2-AP1S1-KO cells reversed these abnormalities, whereas expression of AP1S1 that contained either missense mutation did not. Our data indicate that loss of AP1S1 function causes an intestinal epithelial barrier defect.

Loss of AP1S1 disrupts epithelial polarity



A CRISPR-screen in intestinal epithelial cells identifies novel factors for polarity and apical transport.
Klee KMC, Hess MW, Lohmüller M, Herzog S, Pfaller K, Müller T, Vogel GF*, Huber LA. Elife. 2023 Jan 20;12:e80135. doi: 10.7554/eLife.80135. Online ahead of print. PMID: 36661306
*Corresponding author

AP1S1 missense mutations cause a congenital enteropathy via an epithelial barrier defect. Klee KMC, Janecke AR, Civan HA, Rosipal Š, Heinz-Erian P, Huber LA, Müller T, Vogel GF.Hum Genet. 2020 Oct;139(10):1247-1259. doi: 10.1007/s00439-020-02168-w. Epub 2020 Apr 18.PMID: 32306098Free PMC article.

Co-existence of ABCB11 and DCDC2 disease: Infantile cholestasis requires both next-generation sequencing and clinical-histopathologic correlation. Vogel GF, Maurer E, Entenmann A, Straub S, Knisely AS, Janecke AR, Müller T.Eur J Hum Genet. 2020 Jun;28(6):840-844. doi: 10.1038/s41431-020-0613-0. Epub 2020 Mar 20.PMID: 32203204

The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development. Demetz E, Tymoszuk P, Hilbe R, Volani C, Haschka D, Heim C, Auer K, Lener D, Zeiger LB, Pfeifhofer-Obermair C, Boehm A, Obermair GJ, Ablinger C, Coassin S, Lamina C, Kager J, Petzer V, Asshoff M, Schroll A, Nairz M, Dichtl S, Seifert M, von Raffay L, Fischer C, Barros-Pinkelnig M, Brigo N, Valente de Souza L, Sopper S, Hirsch J, Graber M, Gollmann-Tepeköylü C, Holfeld J, Halper J, Macheiner S, Gostner J, Vogel GF, Pechlaner R, Moser P, Imboden M, Marques-Vidal P, Probst-Hensch NM, Meiselbach H, Strauch K, Peters A, Paulweber B, Willeit J, Kiechl S, Kronenberg F, Theurl I, Tancevski I, Weiss G.Eur Heart J. 2020 Oct 21;41(40):3949-3959. doi: 10.1093/eurheartj/ehaa140.PMID: 32227235



ÖNB Anniversary Fund 18019, TWF Grant 0404/2386, ÖGKJ research grant



Priv.-Doz. Dr. med. univ. Georg-Friedrich, PhD
Phone: +43 512 504 82184