Molecular pathogenesis of ARPKD

The monogenic Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a most severe disorder of pediatric nephrology and among the most common causes of end stage renal failure in childhood. ARPKD is caused by mutations in the PKHD1 gene encoding the 450 kDa transmembrane protein Fibrocystin (FC). Fibrocystin’s cellular function is very poorly understood.

 

 
 
 
 
 

The overarching aim of our group is to understand the molecular mechanisms underlying cystogenesis and renal fibrosis in PKD with a special focus on the role of FC and FC-associated ciliary proteins. Using multiple screening approaches we recently identified various novel candidates for members of the FC protein complex and are currently characterizing these proteins functionally both in vitro and in vivo. This work examines two main aspects of protein dysfunction in PKD: impaired trafficking to cilia and defective signal transduction from cilia to the cell resulting e.g. in altered expression of transcriptional cell programs.

Our cell biological work is complemented by the recently established European ARPKD patient registry study (www.aregpkd.org). As ARPKD can serve as a model ciliopathy, the combined clinical and cell biological approach will not only substantially broaden our understanding of PKD pathophysiology and ARPKD clinical courses, but will also shed light into common mechanisms of ciliopathies as a whole.

Group leader

PD Dr. med. Max Liebau

Teammembers

  • Claudia Dafinger, PhD
  • Sophie Haumann, MD
  • Amrei Mandel

Selected publications

  1. Ebner K., C. Dafinger, N. Ortiz-Bruechle, F. Koerber, B. Schermer, T. Benzing, J. Dötsch, K. Zerres, L.T. Weber, B.B. Beck, M.C. Liebau. (2017). Challenges in establishing genotype-phenotype correlations in ARPKD: case report on a toddler with two severe PKHD1 mutations. Pediatr Nephrol 32(7):1269-1273.
  2. Ebner K., M. Feldkoetter, G. Ariceta, C. Bergmann, R. Buettner, A. Doyon, A. Duzova, H. Goebel, D. Haffner, B. Hero, B. Hoppe, T. Illig, A. Jankauskiene, N. Klopp, J. König, M. Litwin , D. Mekahli, B. Ranchin, A. Sander, S. Testa, L.T. Weber, D. Wicher, A. Yuzbasioglu, K. Zerres, J. Dötsch, F. Schaefer F, M.C. Liebau; ESCAPE Study Group; GPN Study Group (2015). Rationale, design and objectives of ARegPKD, a European ARPKD registry study. BMC Nephrol 16:22.
  3. Liebau M.C., F. Braun, K. Höpker, C. Weitbrecht, V. Bartels, R.-U. Müller, S. Brodesser, M.A. Saleem, T. Benzing, B. Schermer, M. Cybulla, C.E. Kurschat (2013). Dysregulated autophagy contributes to podocyte damage in Fabry's disease. PLoS One 8(5):e63506.
  4. Chaki, M., R. Airik, A.K. Ghosh, R.H. Giles, R. Chen, G.G. Slaats, H. Wang, T.W. Hurd, W. Zhou, A. Cluckey, H.Y. Gee, G. Ramaswami, C.J. Hong, B.A. Hamilton, I. Cervenka, R.S. Ganji, V. Bryja, H.H. Arts, J. van Reeuwijk, M.M. Oud, S.J. Letteboer, R. Roepman, H. Husson, O. Ibraghimov-Beskrovnaya, T. Yasunaga, G. Walz, L. Eley, J.A. Sayer, B. Schermer, M.C. Liebau, T. Benzing, (…) , E.A. Otto, and F. Hildebrandt (2012). Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell 150(3): p. 533-48.
  5. Liebau, M.C., K. Hopker, R.U. Muller, I. Schmedding, S. Zank, B. Schairer, F. Fabretti, M. Hohne, M.P. Bartram, C. Dafinger, M. Hackl, V. Burst, S. Habbig, H. Zentgraf, A. Blaukat, G. Walz, T. Benzing, and B. Schermer (2011). Nephrocystin-4 regulates Pyk2-induced tyrosine phosphorylation of nephrocystin-1 to control targeting to monocilia. J Biol Chem 286(16): p. 14237-45.
  6. Dafinger, C., M.C. Liebau, S.M. Elsayed, Y. Hellenbroich, E. Boltshauser, G.C. Korenke, F. Fabretti, A.R. Janecke, I. Ebermann, G. Nurnberg, P. Nurnberg, H. Zentgraf, F. Koerber, K. Addicks, E. Elsobky, T. Benzing, B. Schermer, and H.J. Bolz (2011). Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics. J Clin Invest 121(7): p. 2662-7.
  7. Ebermann, I., J.B. Phillips, M.C. Liebau, R.K. Koenekoop, B. Schermer, I. Lopez, E. Schafer, A.F. Roux, C. Dafinger, A. Bernd, E. Zrenner, M. Claustres, B. Blanco, G. Nurnberg, P. Nurnberg, R. Ruland, M. Westerfield, T. Benzing, and H.J. Bolz (2010). PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome. J Clin Invest 120(6): p. 1812-23.