Talk abstracts

Talk on Friday 03:30-03:45pm submitted by Faegheh Jafarifar

Phenotypic analysis of a mouse model of human MOPD I

Faegheh Jafarifar (Molecular Genetics, Cleveland Clinic, Lerner Research Institute), David E. Symer (Department of Internal Medicine, Human Cancer Genetics Program, Departments of Molecular Virology, Immunology and Medical Genetics, Ohio State University ), Richard A. Padgett (Molecular Genetics, Cleveland Clinic, Lerner Research Institute)

Abstract:
We recently identified the molecular basis of a devastating human developmental disorder called microcephalic osteodysplastic primordial dwarfism type 1 (MOPD I) which is caused by mutations in the minor spliceosomal snRNA U4atac. The MOPD I mutations disrupt U12-dependent, minor spliceosomal function and cause aberrant pre-mRNA splicing of downstream target genes. MOPD I is a severely debilitating disorder and the affected infants suffer from severe growth retardation, multiple skeletal abnormalities, abnormal brain development and typically early death. We found that splicing of most genes containing minor class introns is significantly disrupted in patient fibroblast cells. MOPD I is very rare and clinical material is difficult to obtain. Therefore, the aberrantly spliced target genes as well as the individual downstream effects that contribute to the various MOPD I phenotypes are unknown. In order to address these issues and to study the phenotypic consequences of MOPD I mutations of U4atac snRNA in vivo, we have generated MOPD I mouse models. Two human mutations, G51A and G55A were knocked in to the mouse U4atac snRNA gene. Homozygous G51A/G51A mice were more severely affected than human patients with most mice showing embryonic lethality. By contrast, MOPD I homozygous G55A/G55A mice were nearly wild type. Importantly, the phenotype of the compound heterozygous G51A/G55A mutant mice was similar to human MOPD I patients. They were small and displayed craniofacial and long bone malformations. An unexpected phenotype of these mutants was that they developed diabetes due to poor pancreatic beta cell development or survival. Further studies are under way to define the developmental defects behind these phenotypes and to link these to the underlying splicing aberrations.

Keywords: Minor spliceosome , MOPD I , RNA disease