Philip J. Mason, Ph.D.

Phil Mason
  • Professor
    • Department of Medicine
      • Hematology Division
    • Department of Genetics
  • Research interests
    • Inherited aplastic anemias
    • Dyskeratosis congenita
    • Telomerase

Research

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.

Telomerase

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

Biographical Sketch

Education

1976 BSc (Hons) Class 1 in Biological Sciences, specialising in Genetics, University of Edinburgh, Scotland
1976-1979 Postgraduate research, laboratory of Dr. John Bishop, Department of Genetics, University of Edinburgh, Scotland
1980 PhD awarded, "The cloning of polyadenylated ribonucleic acid sequences from Drosophila"

Academic Positions & Employment

1971-1972 Junior technician, MRC Human Biochemical Genetics Unit, University College, London
1979-1980 Post doctoral research fellow, Dr. John Bishop's laboratory, Department of Genetics, University of Edinburgh, Scotland
1980-1982 European Molecular Biology Organisation long-term fellow, laboratory of Prof. Alfred Tissieres, Department of Molecular Biology, University of Geneva, Switzerland
1982-1985 Research fellow, Developmental Gene Expression Laboratory (Department head: Dr. Jeffrey Williams), Imperial Cancer Research Fund, Mill Hill Laboratories, London
1985-1992 Lecturer, Department of Haematology. Royal Postgraduate Medical School, Hammersmith Hospital, London
1992-2000 Senior Lecturer, Department of Haematology. Royal Postgraduate Medical School, Hammersmith Hospital, London
2000-2003 Reader in Molecular Genetics. Department of Haematology. Imperial College School of Medicine, Hammersmith Hospital, London
2004-2007 Associate Professor (Research Track), Department of Medicine, Division of Hematology, Washington University, St. Louis, MO
2007-present Research Professor, Department of Medicine, Division of Hematology, Washington University, St. Louis, MO
2007-present Professor, Department of Genetics, Washington University, St. Louis, MO

Awards & Invited Lectures

1980 EMBO long term fellowship
1987 Organiser, Royal Postgraduate School Short Course "Techniques in Human Molecular Genetics," Royal Postgraduate School, London
1989 Organiser. EMBO Practical Course "Modern Techniques in Human Genetics," Royal Postgraduate School, London
1995 Invited lecturer, Seminario Internacional de Farmaceuticos, Sao Paulo. Brazil
2003 Edward J Mallinckrodt Jr Foundation Award
2004 Invited lecturer, British Association for Cancer Research, Conference on Stem Cells and Telomerase: Targets for Transformation & Therapeutic Applications, Cyprus
2005 Invited Lecturer, The Ribo-Club, Sherbrooke, Quebec, Canada
2006 Invited Lecturer, Beijing Union Medical College, Beijing, China
2006 Invited Lecturer, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science, Tianjin, China
2006 Invited Lecturer, Instituto de Investigaciones Biomedicas CSIC/UAM, Madrid, Spain

Academic Societies

  British Society of Haematology
  Genetics Society
  Biochemical Society
  British Society of Parasitology
  American Society of Hematology
  RNA Society

Updated: March 27, 2008

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