Poster abstracts

Poster number 143 submitted by Kevin Yum

Identifying the Role of Muscleblind-Like Protein 1 in Myotonic Dystrophy Type 1 Pathogenesis and Postnatal Liver Development

Kevin Yum (Department of Biochemistry, University of Illinois at Urbana-Champaign), Amruta Bhate (Department of Biochemistry, University of Illinois at Urbana-Champaign), Anthony Chau (Department of Biochemistry, University of Illinois at Urbana-Champaign), Sandip Chorghade (Department of Biochemistry, University of Illinois at Urbana-Champaign), Auinash Kalsotra (Department of Biochemistry, University of Illinois at Urbana-Champaign)

Abstract:
Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a microsatellite repeat expansion in the 3’-untranslated region of the dystrophia myotonica-protein kinase gene. In DM1, the repeat-bearing transcripts promote misregulated alternative splicing (AS) in cardiac and skeletal muscle by sequestering the muscleblind-like (MBNL) proteins in the nucleoplasm. Here we demonstrate that MBNL1 knockout (KO) liver closely resembles the aberrant AS patterns previously found in DM1 striated muscle. MBNL1-dependent splicing defects were determined using RT-PCR analysis and unique adult-to-embryonic splicing changes were discovered in MBNL1 KO liver. Additionally, histological analysis of MBNL1 KO liver showed disrupted hepatic architecture and ballooning degeneration of hepatocytes. These results indicate that MBNL1 is required for maintenance of adult liver splicing patterns and loss of MBNL1 function leads to defects that are reminiscent of DM1 pathology. To further validate our hypothesis that loss of MBNL1 function is responsible for splicing misregulation in DM1 liver, recombinant FLAG-tagged MBNL1 adenoviruses were constructed to overexpress MBNL1 in a liver-specific DM1 mouse model. Our preliminary data suggest that loss of MBNL1 function impairs postnatal AS transition of DM1 liver, prompting further evaluation of various tissues other than skeletal and cardiac muscle.

Keywords: myotonic dystrophy, muscleblind-like protein, alternative splicing