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Abstract: SA-PO551

Biallelic Variants in TULP3 Cause Variable Onset Liver Cirrhosis and Kidney Failure With Defective Ciliary Cargo Composition and DNA Damage Repair

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Sayer, John Andrew, Newcastle University Faculty of Medical Sciences, Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
  • Devane, John, Albert-Ludwigs-Universitat Freiburg Medizinische Fakultat, Freiburg, Baden-Württemberg, Germany
  • Ott, Elisabeth B., Albert-Ludwigs-Universitat Freiburg Medizinische Fakultat, Freiburg, Baden-Württemberg, Germany
  • Epting, Daniel, Albert-Ludwigs-Universitat Freiburg Medizinische Fakultat, Freiburg, Baden-Württemberg, Germany
  • Olinger, Eric Gregory, Newcastle University Faculty of Medical Sciences, Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
  • Bergmann, Carsten, Albert-Ludwigs-Universitat Freiburg Medizinische Fakultat, Freiburg, Germany
Background

Several pathways governed by the primary cilium have been linked to human disease. Among them is autosomal recessive polycystic kidney disease (ARPKD), characterized by early-onset kidney failure in association with ductal plate malformation and hepatic fibrosis. So far, only two ciliary genes have been implicated in the ARPKD spectrum.

Methods

We used a combination of massive parallel sequencing with clinical, imaging and histopathological analysis in unsolved patients with features of ARPKD. Mechanistic studies were conducted in different cell models including patient-derived primary cells. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project (100kGP) (http://www.genomicsengland.co.uk).

Results

We report a 68-year-old female with a history of liver transplantation (aged 41 years) due to biliary cirrhosis and chronic kidney disease with multiple small cortical and medullary kidney cysts. Through whole genome sequencing analysis, we identified a homozygous missense variant affecting a functionally relevant amino acid in TULP3, encoding tubby-like protein 3 implicated in ciliary trafficking of various membrane proteins. Through 100kGP and international collaborators, a further 7 families with matching phenotypes and biallelic TULP3 variants were detected. Patients (n=15) showed a wide range of disease onset (4-33 years) and presented with progressive liver fibrosis, fibrocystic kidney disease and histologically atypical hypertrophic cardiomyopathy. End-stage liver and kidney disease mostly occurred in adulthood. In several patient-derived cell systems, we identified disrupted ciliary cargo composition, including several proteins previously linked with hepatic fibrosis and cystic kidneys in humans and mice. Ex vivo pathway analyses demonstrated aberrant DNA damage repair and upregulation of profibrotic pathways with gene clusters for hypertrophic cardiomyopathy, WNT and TGF-β signalling.

Conclusion

These findings identify a novel monogenic cause for a recessive progressive degenerative disease of major organs including the kidney in which affected individuals may benefit from early detection and improved clinical management.