Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome associated with a predisposition to cancer. DC is diagnosed by the triad of abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia and gastrointestinal, genitourinary, neurological, and skeletal abnormalities are often present. X-linked DC is due to mutations in the DKC1 gene encoding the nucleolar protein, dyskerin, a component of small nucleolar RNA particles active in the pseudouridylation of specific residues in nascent ribosomal RNA (rRNA) molecules. Dyskerin also forms part of the telomerase complex responsible for synthesizing the telomere repeats at the ends of chromosomes. The relative contributions of deficient rRNA synthesis and deficient telomere maintenance to the pathology of X-linked DC is unknown. We hypothesize that bone marrow failure in X-linked DC is a consequence of both decreased efficiency of rRNA production and defective telomere maintenance, and that epithelial cancers form because rapid proliferation of epithelial cells with low telomerase levels produces genomic instability and DNA damage. To test our hypotheses we will generate mice with specific mutations in distinct functional domains of the murine homologue Dkc1. These mutations have been found in DC patients and cause disease of varying severity. The Dkc1 mutant mice will be monitored for the development of disease including bone marrow failure and cancer development throughout their lifetime and over several generations. The effect of the mutations on rRNA processing and telomerase function/telomere maintenance will be determined. Finally, we will study the effect of the Dkc1 mutations in the context of short telomeres by breeding the Dkc1 mutant mice with short telomere telomerase deficient mice. Similarly, we will breed Dkc1 mutant mice with mice mutated at the tumor suppressor p53 locus. Alterations of the phenotype in double transgenic mice will be examined at the cellular level and in the entire animal. In particular we will examine the time of onset and severity of bone marrow failure and the frequency, time of occurrence and histology of cancers. We believe that mice are an ideal model to investigate the two possible pathways of dyskerin function. Laboratory mice have longer telomeres than humans so pathology due to a defect in ribosome biogenesis should appear in early generations whereas pathology due to telomere defects will only become evident after several generations of inbreeding or after the breeding with mice with short telomeres. Through these studies we hope to increase our understanding of the pathogenesis of DC and gain new insights into the importance of ribosomal biogenesis and telomere maintenance in human disease. The availability of a mouse model for DC will provide us with a powerful tool to test new therapeutic agents for the treatment of DC and possibly other disorders caused by altered RNA processing or defective telomere maintenance.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Hematopoiesis Study Section (HP)
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Mietz, Judy
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
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Perdigones, Nieves; Perin, Juan C; Schiano, Irene et al. (2016) Clonal hematopoiesis in patients with dyskeratosis congenita. Am J Hematol 91:1227-1233
Gu, Bai-Wei; Apicella, Marisa; Mills, Jason et al. (2015) Impaired Telomere Maintenance and Decreased Canonical WNT Signaling but Normal Ribosome Biogenesis in Induced Pluripotent Stem Cells from X-Linked Dyskeratosis Congenita Patients. PLoS One 10:e0127414
Cai, Xiongwei; Gao, Long; Teng, Li et al. (2015) Runx1 Deficiency Decreases Ribosome Biogenesis and Confers Stress Resistance to Hematopoietic Stem and Progenitor Cells. Cell Stem Cell 17:165-77
Ge, Jingping; Apicella, Marisa; Mills, Jason A et al. (2015) Dysregulation of the Transforming Growth Factor ? Pathway in Induced Pluripotent Stem Cells Generated from Patients with Diamond Blackfan Anemia. PLoS One 10:e0134878
Reeves, D A; Gu, B W; Bessler, M et al. (2015) Variations in reactive oxygen species between mouse strains. Blood Cells Mol Dis 55:189-90
Mason, Philip J; Bessler, Monica (2015) mRNA deadenylation and telomere disease. J Clin Invest 125:1796-8
Mason, Philip J; Bessler, Monica (2013) Poikiloderma with neutropenia: beginning at the end. Blood 121:872-4
Mason, Philip J; Perdigones, Nieves; Bessler, Monica (2013) Using induced human pluripotent stem cells to study Diamond-Blackfan anemia: an outlook on the clinical possibilities. Expert Rev Hematol 6:627-9
Garçon, Loïc; Ge, Jingping; Manjunath, Shwetha H et al. (2013) Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients. Blood 122:912-21
Gu, Bai-Wei; Ge, Jingping; Fan, Jian-Meng et al. (2013) Slow growth and unstable ribosomal RNA lacking pseudouridine in mouse embryonic fibroblast cells expressing catalytically inactive dyskerin. FEBS Lett 587:2112-7

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