Abstract
Abstract
RMRP was the first non-coding nuclear RNA gene implicated in a disease. Its mutations cause cartilage-hair hypoplasia (CHH), an autosomal recessive skeletal dysplasia with growth failure, immunodeficiency, and a high risk for malignancies. This study aimed to gain further insight into the role of RNA Component of Mitochondrial RNA Processing Endoribonuclease (RMRP) in cellular physiology and disease pathogenesis. We combined transcriptome analysis with single-cell analysis using fibroblasts from CHH patients and healthy controls. To directly assess cell cycle progression, we followed CHH fibroblasts by pulse-labeling and time-lapse microscopy. Transcriptome analysis identified 35 significantly upregulated and 130 downregulated genes in CHH fibroblasts. The downregulated genes were significantly connected to the cell cycle. Multiple other pathways, involving regulation of apoptosis, bone and cartilage formation, and lymphocyte function, were also affected, as well as PI3K-Akt signaling. Cell-cycle studies indicated that the CHH cells were delayed specifically in the passage from G2 phase to mitosis. Our findings expand the mechanistic understanding of CHH, indicate possible pathways for therapeutic intervention and add to the limited understanding of the functions of RMRP.
Funder
Cancerfonden
Knut och Alice Wallenbergs Stiftelse
Vetenskapsrådet
Publisher
Springer Science and Business Media LLC
Reference36 articles.
1. Makitie, O. & Kaitila, I. Cartilage-hair hypoplasia–clinical manifestations in 108 Finnish patients. European journal of pediatrics 152, 211–217 (1993).
2. Ridanpaa, M. et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell 104, 195–203 (2001).
3. Vakkilainen, S., Taskinen, M., Klemetti, P., Pukkala, E. & Mäkitie, O. A 30-year prospective follow-up study reveals risk factors for early death in cartilage-hair hypoplasia. Front Immunol 16 July 2019.
4. Thiel, C. T. & Rauch, A. The molecular basis of the cartilage-hair hypoplasia-anauxetic dysplasia spectrum. Best Pract Res Clin Endocrinol Metab 25, 131–142,
https://doi.org/10.1016/j.beem.2010.08.004
(2011).
5. Cai, T., Aulds, J., Gill, T., Cerio, M. & Schmitt, M. E. The Saccharomyces cerevisiae RNase mitochondrial RNA processing is critical for cell cycle progression at the end of mitosis. Genetics 161, 1029–1042 (2002).
Cited by
20 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献