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Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations

Lookup NU author(s): Carina Oliva, Laura Powell, Dr Ian Wilson, Dr Sarah RiceORCiD, Dr Colin Miles, Dr Katrina Wood, Professor John SayerORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022 The Author(s). Organ fibrosis is a shared endpoint of many diseases, yet underlying mechanisms are not well understood. Several pathways governed by the primary cilium, a sensory antenna present on most vertebrate cells, have been linked with fibrosis. Ciliopathies usually start early in life and represent a considerable disease burden. We performed massively parallel sequencing by using cohorts of genetically unsolved individuals with unexplained liver and kidney failure and correlated this with clinical, imaging, and histopathological analyses. Mechanistic studies were conducted with a vertebrate model and primary cells. We detected bi-allelic deleterious variants in TULP3, encoding a critical adaptor protein for ciliary trafficking, in a total of 15 mostly adult individuals, originating from eight unrelated families, with progressive degenerative liver fibrosis, fibrocystic kidney disease, and hypertrophic cardiomyopathy with atypical fibrotic patterns on histopathology. We recapitulated the human phenotype in adult zebrafish and confirmed disruption of critical ciliary cargo composition in several primary cell lines derived from affected individuals. Further, we show interaction between TULP3 and the nuclear deacetylase SIRT1, with roles in DNA damage repair and fibrosis, and report increased DNA damage ex vivo. Transcriptomic studies demonstrated upregulation of profibrotic pathways with gene clusters for hypertrophic cardiomyopathy and WNT and TGF-β signaling. These findings identify variants in TULP3 as a monogenic cause for progressive degenerative disease of major organs in which affected individuals benefit from early detection and improved clinical management. Elucidation of mechanisms crucial for DNA damage repair and tissue maintenance will guide novel therapeutic avenues for this and similar genetic and non-genomic diseases.

Publication metadata

Author(s): Devane J, Ott E, Olinger EG, Epting D, Decker E, Friedrich A, Bachmann N, Renschler G, Eisenberger T, Briem-Richter A, Grabhorn EF, Powell L, Wilson IJ, Rice SJ, Miles CG, Wood K, Trivedi P, Hirschfield G, Pietrobattista A, Wohler E, Mezina A, Sobreira N, Agolini E, Maggiore G, Dahmer-Heath M, Yilmaz A, Boerries M, Metzger P, Schell C, Grunewald I, Konrad M, Konig J, Schlevogt B, Sayer JA, Bergmann C

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2022

Volume: 109

Issue: 5

Pages: 928-943

Print publication date: 05/05/2022

Online publication date: 08/04/2022

Acceptance date: 22/03/2022

Date deposited: 24/05/2022

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2022.03.015

PubMed id: 35397207


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Funder referenceFunder name
Paed_RP_001_20180925Kidney Research UK (was National Kidney Research Fund)