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My research is directed to understanding the genetics and pathogenesis of inherited bone marrow failure syndromes. We are particularly interested in 2 of these, namely dyskeratosis congenita and Diamond Blackfan Anemia. Though these syndromes are relatively rare we expect that the mechanisms underlying these conditions will help us understand more common conditions such as idiopathic aplastic anemia and myelodysplastic syndrome. Moreover since these diseases are associated with an increased incidence of malignancy we hope to learn about mechanisms of carcinogenesis.

Dyskeratosis congenita has X-linked, autosomal dominant and recessive forms. We have identified a gene DKC1, which encodes a protein called dyskerin, that is responsible for the X-linked form of the disease. Dyskerin is a 57kD nucleolar protein that is a key component of snoRNP complexes -- ribonucleoprotein particles that modify ribosomal RNA. Dyskerin contains pseudouridine synthase activity and with the help of the snoRNA guide changes specific uridines in rRNA pseudouridines, a process essential for rRNA processing and ribosome biogenesis. Dyskerin also associates with telomerase RNA, TERC, an essential telomerase component that provides the template for the synthesis of the telomere repeats that are part of the telomeres, nucleoprotein caps at the ends of chromosomes. Because dyskerin has these two quite different functions it is important to determine which is important in the pathogenesis of dyskeratosis congenita. We are approaching this question by using gene targeting to introduce mutations into the mouse Dkc1 gene. We then study ribosome biogenesis and telomere maintenance in mouse cells and in mice. Our studies so far have shown that dyskerin is essential for embryonic development and that mutations that cause DC in humans cause variable ribosome and telomerase defects in mice. We have found that dyskerin may not be essential for nonproliferating cells but that it is important for cell proliferation. We are breeding our mutant mice with mice with short telomeres to generate a strain of mice with features of the human disease. We are also breeding with p53 mutant mice to study the relationship between ribosome biogenesis, the cell cycle and the p53 pathway.

Diamond Blackfan Anemia is a pure red cell aplasia which presents usually in childhood, sometimes with a variety of associated developmental abnormalities. 25% of cases are due to mutations in RPS19, encoding small ribosomal protein 19. It is not known how mutations in a ubiquitously expressed protein can cause a disease resulting from failure of a specific cell type. Our hypothesis is that haploinsufficiency of RPS19 causes reduction in the efficiency of ribosome biogenesis and while most tissues are not affected red cell precursors are blocked in their development. We have shown that cells with low RPS19 levels induced by RNAi have severely inhibited ribosome biogenesis probably due to failure to produce 18S rRNA. We are now making mutations in mouse Rps19 to try and recapitulate the disease in mice and developing a culture system to study RPS19 function in erythropoiesis.

The relationship between H/ACA snoRNPs and telomerase RNPs Telomerase RNA has a H/ACA box sequence at its 3' end and is associated with the same 4 proteins that are present in the snoRNP. Other proteins are present in the telomerase complex including the telomerase reverse transcriptase TERT. From: Mason PJ, Wilson DB, Bessler M Dyskeratosis congenita -- a disease of dysfunctional telomere maintenance. Curr Mol Med 2005 Mar;5(2):159-70

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Updated: March 27, 2008