B04 Identification of TULP3 mutations in patients with cystic kidney disease and related ciliopathies

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27

  • B01
    • Walz
    • Kammerer
  • B02
    • Köttgen
  • B04
    • Bergmann
  • B06
    • Lausch
    • Schmidts
  • B07
    • Lienkamp
    • Arnold

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29

  • Z01
    • Nitschke
    • Eimer
  • Z02
    • Brox
    • Ronneberger
Carsten Bergmann

Carsten Bergmann

Principal investigator of

Cystic kidney disorders such as polycystic kidney disease (ADPKD/ARPKD) and nephronophthisis (NPHP) play a central role in the elucidation of ciliopathies and practically all cilia-related disorders can show renal cysts. NPHP is the leading genetic cause of renal failure in children and young adults and often presents with extrarenal manifestations of e.g. eye, liver, heart and brain. Cystic disease is centered on the kidney and liver, but can also manifest in other organs. Autosomal dominant PKD (ADPKD) is the most frequent life-threatening genetic disorder and typically shows adult disease onset. However, in a small subset of patients ADPKD present with an early and severe phenotype with perinatal morbidity and mortality, clinically often indistinguishable from recessive PKD (ARPKD). Reasons for variable disease expression are largely unknown, but key for a better disease understanding. 

Recently, we identified TULP3 mutations in patients. TULP3 encodes a member of the tubby family of bipartite transcription factors that acts as a negative Sonic hedgehog regulator. Together with the IFT-A ciliary transport machinery, it promotes trafficking of G protein-coupled receptors to cilia. Based on a large cohort of clinically well-characterized patients with cystic kidney disorders and related ciliopathies, we propose to use a multi-disciplinary approach to better understand the role of TULP3 in cystic kidney disease. Towards this goal, we will 1) characterize the mutational and phenotypic spectrum of TULP3-related disease, 2) validate human genotypes in zebrafish embryos as a model organism, and finally 3) translate our genetic findings into mechanistic studies, aiming to understand the cellular perturbations caused by TULP3 mutations. A comprehensive knowledge of the contribution of TULP3 to hereditary diseases will be crucial for accurate diagnosis, genetic counseling and the management of patients.