Harry C. Dietz, M.D.
One focus of the laboratory is the investigation of the molecular etiology and pathogenesis of inherited forms of cardiovascular disease. The phenotype under most intense scrutiny is the Marfan syndrome (MFS), a systemic disorder of connective tissue with cardinal manifestations in the ocular, skeletal, and cardiovascular systems. In 1991 we demonstrated that mutations in FBN1 (encoding the matrix protein fibrillin-1) cause MFS. Use of engineered animal models of disease has revealed that fibrillin-1 regulates activation and signaling of multiple cytokines including TGFb and that perturbation of this process culminates in abnormal tissue morphogenesis. The current emphasis is to define the role of cytokine dysregulation in the multi-system pathogenesis of MFS and to exploit this knowledge in the creation of novel therapeutic strategies. Related projects in the lab include elucidation of the etiology and pathogenesis of familial tetralogy of Fallot, bicommissural aortic valve with aneurysm, and age-dependent vessel wall degeneration. The lab also studies the processes by which the cell recognizes and selectively degrades defective transcripts before they generate potentially deleterious truncated proteins. Our interest in nonsense-mediated RNA decay (NMD) stems from the observation that this process can modulate selective dominant-negative phenotypes. Our current emphasis includes definition of the mechanism by which NMD alters the intranuclear performance of nonsense transcripts including stability, splicing, and trafficking. We are also examining the basic physiologic importance of mRNA surveillance that manifests with complete evolutionary conservation of the function. Such insight may provide both incentive and strategy for productive pharmacologic modulation of the process in the treatment of human genetic disease.
- Noensie F and Dietz HC. A strategy for disease gene identification through nonsense-mediated mRNA decay inhibition. Nature Biotechnology19:434-439, 2001.
- Mendell JT and Dietz HC. When the Message Goes Awry: Disease-Producing Mutations that Influence mRNA Content and Performance. Cell 107:411-414, 2001.
- Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC. Association of human aging with functional variant of klotho. PNAS 99:856-861, 2002.
- Frischmeyer PA, van Hoof A, O’Donnell K, Guerrerio AL, Parker R, Dietz HC. An mRNA surveillance mechanism that eliminates transcripts lacking termination codons. Science 295(5563):2258-61, 2002.
- Mendell JT, ap Rhys CMJ, Dietz HC. Separable roles for rent1/hUpf1 in altered splicing and decay of nonsense transcripts. Science 298:419-422, 2002.
- Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, Ramirez F, Sakai L, Dietz HC. Dysregulation of TGF activation contributes to pathogenesis of Marfan syndrome. Nature Genet 33(3):407-411, 2003.
- Judge DP, Biery NJ, Keene DR, Geubtner J, Myers L, Huso DL, Sakai LY, Dietz HC. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest 114:172-81, 2004.
- Mendell JT, Sharifi NA, Meyer JL, Martinez-Murillo F, Dietz HC. Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nature Genet 2004. (In press)