Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations
Devane, John Ott, Elisabeth Olinger, Eric G Epting, Daniel Decker, Eva Friedrich, Anja Bachmann, Nadine Renschler, Gina Eisenberger, Tobias Briem-Richter, Andrea
Devane, John
Ott, Elisabeth
Olinger, Eric G
Epting, Daniel
Decker, Eva
Friedrich, Anja
Bachmann, Nadine
Renschler, Gina
Eisenberger, Tobias
Briem-Richter, Andrea
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Affiliation
Medical Center-University of Freiburg; Newcastle University; Medizinische Genetik Mainz; University Medical Center Hamburg-Eppendorf; The Newcastle upon Tyne Hospitals NHS Foundation Trust; University of Birmingham; University Hospitals Birmingham NHS Foundation Trust; University Health Network, Toronto; IRCCS Bambino Gesù Children's Hospital; Johns Hopkins University School of Medicine; University of Pennsylvania Perelman School of Medicine; University Hospital Münster; The German Cancer Consortium
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Publication date
2022-04-08
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Abstract
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.
Citation
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; Genomics England Research Consortium; 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, Grünewald I, Konrad M, König J, Schlevogt B, Sayer JA, Bergmann C. Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations. Am J Hum Genet. 2022 May 5;109(5):928-943. doi: 10.1016/j.ajhg.2022.03.015. Epub 2022 Apr 8.
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Article