PUBLICATION
Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations
- Authors
- Devane, J., Ott, E., Olinger, E.G., Epting, D., Decker, E., Friedrich, A., Bachmann, N., Renschler, G., Eisenberger, T., Briem-Richter, A., Grabhorn, E.F., Powell, L., Wilson, I.J., Rice, S.J., Miles, C.G., 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, J.A., Bergmann, C.
- ID
- ZDB-PUB-220410-4
- Date
- 2022
- Source
- American journal of human genetics 109(5): 928-943 (Journal)
- Registered Authors
- Bergmann, Carsten, Epting, Daniel, Ott, Elisabeth B.
- Keywords
- ciliopathy, genetic disease burden, hypertrophic cardiomyopathy, internal medicine genetics, kidney failure, liver fibrosis, organ fibrosis, tubby-like proteins
- MeSH Terms
-
- Animals
- Kidney
- Cardiomyopathy, Hypertrophic*/metabolism
- Cilia*/genetics
- Cilia*/metabolism
- Liver
- Mutation/genetics
- Humans
- Intracellular Signaling Peptides and Proteins/genetics
- Fibrosis
- Zebrafish/genetics
- PubMed
- 35397207 Full text @ Am. J. Hum. Genet.
Citation
Devane, J., Ott, E., Olinger, E.G., Epting, D., Decker, E., Friedrich, A., Bachmann, N., Renschler, G., Eisenberger, T., Briem-Richter, A., Grabhorn, E.F., Powell, L., Wilson, I.J., Rice, S.J., Miles, C.G., 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, J.A., Bergmann, C. (2022) Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations. American journal of human genetics. 109(5):928-943.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping