Molecular pathogenesis of ARPKD

The monogenic Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a 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 my group is to understand the molecular mechanisms underlying cystogenesis as well as kidney and liver fibrosis in PKD, with a particular 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 FC-regulated proteins. We are currently characterizing the consequences of FC dysfunction both in vitro and in vivo. This work examines the main molecular aspects in PKD: we examine impaired trafficking to cilia and defective signal transduction from cilia to the cell, resulting, e.g., in altered expression and activity of transcriptional cell programs. We furthermore study the effects of FC dysfunction on cellular metabolism.

Our cell biological work is complemented by the ARPKD patient registry study ARegPKD (www.aregpkd.org), which has gathered a large dataset of longitudinal clinical data. Over the past years, we have thus laid the foundation for translational research on ARPKD. 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 on common mechanisms of ciliopathies as a whole.

SELECTED PUBLICATIONS

Dafinger, C., Benzing, T., Dotsch, J., Schermer, B., and Liebau, M.C. (2021) Targeted deletion of Ruvbl1 results in severe defects of epidermal development and perinatal mortality. Mol Cell Pediatr, 8(1): 1.

Burgmaier, K., Kilian, S., Arbeiter, K., Atmis, B., Buscher, A., Derichs, U., Dursun, I., Duzova, A., Eid, L.A., Galiano, M., Gessner, M., Gokce, I., Haeffner, K., Hooman, N., Jankauskiene, A., Korber, F., Longo, G., Massella, L., Mekahli, D., Milosevski-Lomic, G., Nalcacioglu, H., Rus, R., Shroff, R., Stabouli, S., Weber, L.T., Wygoda, S., Yilmaz, A., Zachwieja, K., Zagozdzon, I., Dotsch, J., Schaefer, F., Liebau, M.C., and Consortium, A.R. (2021) Early childhood height-adjusted total kidney volume as a risk marker of kidney survival in ARPKD. Sci Rep, 11(1): 21677.

Burgmaier, K., Brinker, L., Erger, F., Beck, B.B., Benz, M.R., Bergmann, C., Boyer, O., Collard, L., Dafinger, C., Fila, M., Kowalewska, C., Lange-Sperandio, B., Massella, L., Mastrangelo, A., Mekahli, D., Miklaszewska, M., Ortiz-Bruechle, N., Patzer, L., Prikhodina, L., Ranchin, B., Ranguelov, N., Schild, R., Seeman, T., Sever, L., Sikora, P., Szczepanska, M., Teixeira, A., Thumfart, J., Uetz, B., Weber, L.T., Wuhl, E., Zerres, K., group, E.S., group, G.P.N.s., Dotsch, J., Schaefer, F., Liebau, M.C., and consortium, A.R. (2021) Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants. Kidney Int, 100(3): 650-659.

Dafinger, C., Mandel, A.M., Braun, A., Gobel, H., Burgmaier, K., Massella, L., Mastrangelo, A., Dotsch, J., Benzing, T., Weimbs, T., Schermer, B., and Liebau, M.C. (2020) The carboxy-terminus of the human ARPKD protein fibrocystin can control STAT3 signalling by regulating SRC-activation. J Cell Mol Med, 24(24): 14633-14638.

Burgmaier, K., Ariceta, G., Bald, M., Buescher, A.K., Burgmaier, M., Erger, F., Gessner, M., Gokce, I., Konig, J., Kowalewska, C., Massella, L., Mastrangelo, A., Mekahli, D., Pape, L., Patzer, L., Potemkina, A., Schalk, G., Schild, R., Shroff, R., Szczepanska, M., Taranta-Janusz, K., Tkaczyk, M., Weber, L.T., Wuhl, E., Wurm, D., Wygoda, S., Zagozdzon, I., Dotsch, J., Oh, J., Schaefer, F., Liebau, M.C., and consortium, A.R. (2020) Severe neurological outcomes after very early bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD). Sci Rep, 10(1): 16025.

Akarkach, A., Burgmaier, K., Sander, A., Hooman, N., Sever, L., Cano, F., Zambrano, P., Bilge, I., Flynn, J.T., Yavascan, O., Valles, P.G., Munarriz, R.L., Patel, H.P., Serdaroglu, E., Koch, V.H., Suarez, A.D.C., Galanti, M., Celedon, C.G., Rebori, A., Kari, J.A., Wong, C.J., Elenberg, E., Rojas, L.F., Warady, B.A., Liebau, M.C., Schaefer, F., and Registry, I. (2020) Maintenance Peritoneal Dialysis in Children With Autosomal Recessive Polycystic Kidney Disease: A Comparative Cohort Study of the International Pediatric Peritoneal Dialysis Network Registry. Am J Kidney Dis, 75(3): 460-464.

Burgmaier, K., Kilian, S., Bammens, B., Benzing, T., Billing, H., Buscher, A., Galiano, M., Grundmann, F., Klaus, G., Mekahli, D., Michel-Calemard, L., Milosevski-Lomic, G., Ranchin, B., Sauerstein, K., Schaefer, S., Shroff, R., Sterenborg, R., Verbeeck, S., Weber, L.T., Wicher, D., Wuhl, E., Dotsch, J., Schaefer, F., and Liebau, M.C. (2019) Clinical courses and complications of young adults with Autosomal Recessive Polycystic Kidney Disease (ARPKD). Sci Rep, 9(1): 7919.

Dafinger, C., Rinschen, M.M., Borgal, L., Ehrenberg, C., Basten, S.G., Franke, M., Hohne, M., Rauh, M., Gobel, H., Bloch, W., Wunderlich, F.T., Peters, D.J.M., Tasche, D., Mishra, T., Habbig, S., Dotsch, J., Muller, R.U., Bruning, J.C., Persigehl, T., Giles, R.H., Benzing, T., Schermer, B., and Liebau, M.C. (2018) Targeted deletion of the AAA-ATPase Ruvbl1 in mice disrupts ciliary integrity and causes renal disease and hydrocephalus. Exp Mol Med, 50(6): 1-17.

Burgmaier, K., Kunzmann, K., Ariceta, G., Bergmann, C., Buescher, A.K., Burgmaier, M., Dursun, I., Duzova, A., Eid, L., Erger, F., Feldkoetter, M., Galiano, M., Gessner, M., Goebel, H., Gokce, I., Haffner, D., Hooman, N., Hoppe, B., Jankauskiene, A., Klaus, G., Konig, J., Litwin, M., Massella, L., Mekahli, D., Melek, E., Mir, S., Pape, L., Prikhodina, L., Ranchin, B., Schild, R., Seeman, T., Sever, L., Shroff, R., Soliman, N.A., Stabouli, S., Stanczyk, M., Tabel, Y., Taranta-Janusz, K., Testa, S., Thumfart, J., Topaloglu, R., Weber, L.T., Wicher, D., Wuhl, E., Wygoda, S., Yilmaz, A., Zachwieja, K., Zagozdzon, I., Zerres, K., Group, E.S., Group, G.P.N.S., Dotsch, J., Schaefer, F., Liebau, M.C., and consortium, A.R. (2018) Risk Factors for Early Dialysis Dependency in Autosomal Recessive Polycystic Kidney Disease. J Pediatr, 199: 22-28 e6.