Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 109, Issue 5, Pages 928-943Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2022.03.015
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Funding
- Swiss National Science Foundation [P2ZHP3_195181, P500PB_206851]
- Kidney Research UK [Paed_RP_001_20180925]
- Versus Arthritis career development fellowship [22615]
- Kidney Research UK
- Northern Counties Kidney Research Fund
- Medical Research Coucil (CiC award)
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [BE 3910/8-1, BE 3910/9-1]
- Collaborative Research Center [SFB 1453, 431984000, SFB 1140, 246781735]
- Federal Ministry of Education and Research (BMBF) [01GM1903I, 01GM1903G]
- DFG [SFB1453, SFB1479, 441891347-S1, SFB1160, TRR167]
- German Federal Ministry of Education and Research by MIRACUM within the Medical Informatics Funding Scheme [FKZ 01ZZ1801B]
- National Institute for Health Research
- NHS England
- Wellcome Trust
- Cancer Research UK
- Medical Research Council
- Swiss National Science Foundation (SNF) [P2ZHP3_195181, P500PB_206851] Funding Source: Swiss National Science Foundation (SNF)
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This study identified bi-allelic deleterious variants in TULP3 as a monogenic cause for progressive degenerative liver fibrosis, fibrocystic kidney disease, and hypertrophic cardiomyopathy. Mechanistic studies using a vertebrate model and primary cells confirmed the disruption of critical ciliary cargo composition. The interaction between TULP3 and the nuclear deacetylase SIRT1, as well as increased DNA damage, were also reported. Transcriptomic studies demonstrated upregulation of profibrotic pathways. These findings have implications for early detection and improved clinical management, as well as potential therapeutic targets for related diseases.
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 WNTand TGF-b 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.
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