Abstract
Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies.
Highlights
Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder first described by Dr Auguste Rothmund in 1868 in his patients who had the characteristic poikilodermatous skin rash and bilateral juvenile cataracts
Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disease characterized by an array of clinical phenotypes affecting multiple tissues
Type 2 RTS patients are prone to developing multiple primary osteosarcomas and have limited chemotherapy options due to organ toxicities or lifetime limits on active agents such as anthracyclines
Summary
Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder first described by Dr Auguste Rothmund in 1868 in his patients who had the characteristic poikilodermatous skin rash and bilateral juvenile cataracts. In 1921 Dr Sydney Thomson reported a similar condition but in association with radial ray defects [1,2,3]. Pathogenic variants in the ANAPC1 and RECQL4 genes have been identified in Type 1 (OMIM #618625) and Type 2 (OMIM #268400) RTS patients, respectively [4,5]. RECQL4 pathogenic variants associated with RTS include nonsense, frameshift, splicing, and intronic deletions, all of which impair RECQL4 cellular function. In contrast to Type 1 RTS patients, who have no elevation in risk of osteosarcoma, Type 2 RTS patients with biallelic RECQL4 pathogenic variants have a significantly elevated lifetime risk of osteosarcoma. While the clinicopathogical features of RTS-associated osteosarcomas are similar to osteosarcomas arising in the general population [6], they occur at an earlier age, and RTS patients are at risk of developing multiple primary tumors
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