NPHP-related polycystic kidney disease in man and mice

• Applicant: Professor Dr. Heymut Omran
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2008 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 58488057

• Final Report Year: 2018

Final Report Abstract

Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes (NPHP1 to -20) have been identified causing either isolated kidney disease or complex multiorgan disorders. At the beginning of the project, only 8 NPHP genes were described to cause Nephropnothisis and related ciliopathies and knowledge about phenotypic variability was limited. Our aim was to increase this knowledge and to further characterize causes and pathogenic mechanisms of NPHP-related polycystic kidney disease in man and mice. Our work helped to identify and functionally characterize novel genes causing Nephronopthisis and related ciliopathies. At the same time, our findings increased the knowledge about NPHP proteins which not only function at the ciliary transition zone, but can also be involved in DNA damage repair. By combining proteomics, genetics and cell biology we defined a ciliary landscape proteins, interactions and complexes which represents a useful resource for Systems Medicine not only in cystic kidney disease research. One important part was the implementation of the NPHP Registry (www.nephreg.de). This registry currently harbours 152 patients and has been utilized to implement interactive online case reporting, communication and education tools. This registry and mouse studies enabled us to analyze the genetic heterogeneity and phenotypic variability (genotype/phenotype correlation) in familial nephronophthisis and related ciliopathies which still is a major challenge. Research continues within the NEOCYST project (Network for early onset cystic kidney disease), financed by the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) and supported by the German Society of pediatric nephrology (GPN). NEOCYST, coordinated by my team in Münster, is a multicenter, interdisciplinary network of clinicians and scientists exploring early onset cystic kidney diseases. The goals of NEOCYST are to increase the knowledge on the epidemiology, the phenotypical spectrum, the underlying genetic and pathophysiological mechanisms as well as the individual prognosis of early onset cystic kidney diseases and thereby to improve the clinical management and counselling of affected patients.

Publications

• Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):1974-1983
  König J, Kranz B, König S, Schlingmann KP, Titieni A, Tönshoff B, Habbig S, Pape L, Häffner K, Hansen M, Büscher A, Bald M, Billing H, Schild R, Walden U, Hampel T, Staude H, Riedl M, Gretz N, Lablans M, Bergmann C, Hildebrandt F, Omran H, Konrad M
  
• Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. Am J Hum Genet. 2008 Apr;82(4):959-70
  Bergmann C, Fliegauf M, Brüchle NO, Frank V, Olbrich H, Kirschner J, Schermer B, Schmedding I, Kispert A, Kränzlin B, Nürnberg G, Becker C, Grimm T, Girschick G, Lynch SA, Kelehan P, Senderek J, Neuhaus TJ, Stallmach T, Zentgraf H, Nürnberg P, Gretz N, Lo C, Lienkamp S, Schäfer T, Walz G, Benzing T, Zerres K, Omran H
  
• Doxycycline accelerates renal cyst growth and fibrosis in the pcy/pcy mouse model of type 3 nephronophthisis, a form of recessive polycystic kidney disease. Histochem Cell Biol. 2009 Aug;132(2):199-210
  Osten L, Kubitza M, Gallagher AR, Kastner J, Olbrich H, de Vries U, Kees F, Lelongt B, Somlo S, Omran H, Witzgall R
  
• Increased expression of secreted frizzled-related protein 4 in polycystic kidneys. J Am Soc Nephrol. 2009 Jan;20(1):48-56
  Romaker D, Puetz M, Teschner S, Donauer J, Geyer M, Gerke P, Rumberger B, Dworniczak B, Pennekamp P, Buchholz B, Neumann HP, Kumar R, Gloy J, Eckardt KU, Walz G
  
• NPHP proteins: gatekeepers of the ciliary compartment. J Cell Biol. 2010 Sep 6;190(5):715-7
  Omran H
  
• Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell. 2012 Aug 3;150(3):533-48
  Chaki M, Airik R, Ghosh AK, Giles RH, Chen R, Slaats GG, Wang H, Hurd TW, Zhou W, Cluckey A, Gee HY, Ramaswami G, Hong CJ, Hamilton BA, Cervenka I, Ganji RS, Bryja V, Arts HH, van Reeuwijk J, Oud MM, Letteboer SJ, Roepman R, Husson H, Ibraghimov- Beskrovnaya O, Yasunaga T, Walz G, Eley L, Sayer JA, Schermer B, Liebau MC, Benzing T, Le Corre S, Drummond I, Janssen S, Allen SJ, Natarajan S, O'Toole JF, Attanasio M, Saunier S, Antignac C, Koenekoop RK, Ren H, Lopez I, Nayir A, Stoetzel C, Dollfus H, Massoudi R, Gleeson JG, Andreoli SP, Doherty DG, Lindstrad A, Golzio C, Katsanis N, Pape L, Abboud EB, Al-Rajhi AA, Lewis RA, Omran H, Lee EY, Wang S, Sekiguchi JM, Saunders R, Johnson CA, Garner E, Vanselow K, Andersen JS, Shlomai J, Nurnberg G, Nurnberg P, Levy S, Smogorzewska A, Otto EA, Hildebrandt F
  
• High-throughput mutation analysis in patients with a nephronophthisis-associated ciliopathy applying multiplexed barcoded array-based PCR amplification and next-generation sequencing. J Med Genet. 2012 Dec;49(12):756-67
  Halbritter J, Diaz K, Chaki M, Porath JD, Tarrier B, Fu C, Innis JL, Allen SJ, Lyons RH, Stefanidis CJ, Omran H, Soliman NA, Otto EA
  
• RPGR mutations might cause reduced orientation of respiratory cilia. Pediatr Pulmonol. 2013 Apr;48(4):352-63
  Bukowy-Bieryłło Z, Ziętkiewicz E, Loges NT, Wittmer M, Geremek M, Olbrich H, Fliegauf M, Voelkel K, Rutkiewicz E, Rutland J, Morgan L, Pogorzelski A, Martin J, Haan E, Berger W, Omran H, Witt M
  
• Situs inversus and ciliary abnormalities: 20 years later, what is the connection? Cilia. 2015 Jan 14;4(1):1
  Pennekamp P, Menchen T, Dworniczak B, Hamada H
  
• An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nat Commun. 2016 May 13;7:11491
  Boldt K, van Reeuwijk J, Lu Q, Koutroumpas K, Nguyen TM, Texier Y, van Beersum SE, Horn N, Willer JR, Mans DA, Dougherty G, Lamers IJ, Coene KL, Arts HH, Betts MJ, Beyer T, Bolat E, Gloeckner CJ, Haidari K, Hetterschijt L, Iaconis D, Jenkins D, Klose F, Knapp B, Latour B, Letteboer SJ, Marcelis CL, Mitic D, Morleo M, Oud MM, Riemersma M, Rix S, Terhal PA, Toedt G, van Dam TJ, de Vrieze E, Wissinger Y, Wu KM, Apic G, Beales PL, Blacque OE, Gibson TJ, Huynen MA, Katsanis N, Kremer H, Omran H, van Wijk E, Wolfrum U, Kepes F, Davis EE, Franco B, Giles RH, Ueffing M, Russell RB, Roepman R; UK10K Rare Diseases Group
  
• Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments. J Am Soc Nephrol. 2016 Jun;27(6):1609-16
  Baisantry A, Bhayana S, Rong S, Ermeling E, Wrede C, Hegermann J, Pennekamp P, Sörensen-Zender I, Haller H, Melk A, Schmitt R
  
• DYNC2H1 mutation causes Jeune syndrome and recurrent lung infections associated with ciliopathy. Clin Respir J. 2017 Mar 3
  Emiralioglu N, Wallmeier J, Olbrich H, Omran H, Ozcelik U