The removal of introns from pre-mRNA transcripts is an essential step in the expression of almost all human genes. we are collaborating with several groups to determine the molecular consequences of human mutations in the U4atac snRNA gene (RNU4ATAC) that are the cause of the rare and severe developmental disorder microcephalic osteodysplastic primordial dwarfism type I (MOPD I). U4atac snRNA is required for the splicing of the minor class U12- dependent introns. Genes containing these introns are poorly spliced in MOPD I patient cells. We hypothesize that the various pathologies seen in MOPD I are caused by reduced splicing or mis-splicing of a small number of U12-dependent intron containing genes. We have developed cell lines and assay systems to investigate the specific defect(s) in splicing caused by the mutations. We will use these cell lines to analyze the effects of the U4atac snRNA mutations on gene expression using RNA-Seq. We will also investigate the functional consequences of additional naturally occurring sequence polymorphisms that we have identified in U4atac and other snRNA genes. Successful completion of these studies will advance our understanding of spliceosomal splicing, define the molecular causes of a human disease and determine the role of U12-dependent splicing in gene expression and development.

Public Health Relevance

The removal of introns by splicing from the primary RNA transcripts of almost all human genes is essential before these transcripts can direct the synthesis of proteins. Mutations in components of the splicing system are known to cause several inherited diseases and to be part of the process of carcinogenesis in some leukemias. In this proposal, we will focus on a severe human developmental disease, microcephalic osteodysplastic primordial dwarfism type I, which is caused by mutations in an RNA component of the splicing machinery. We will determine the mechanism of the splicing defect and characterize the changes in the expression of genes caused by the splicing defect. The goal is to identify the key target genes whose mis- expression causes the various symptoms of the disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular Genetics A Study Section (MGA)
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Bender, Michael T
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Jafarifar, Faegheh; Dietrich, Rosemary C; Hiznay, James M et al. (2014) Biochemical defects in minor spliceosome function in the developmental disorder MOPD I. RNA 20:1078-89
Przychodzen, Bartlomiej; Jerez, Andres; Guinta, Kathryn et al. (2013) Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms. Blood 122:999-1006
Padgett, Richard A (2012) New connections between splicing and human disease. Trends Genet 28:147-54