Transcriptionally-correlated sub-cellular dynamics of MBNL1 during lens development and their implication for the molecular pathology of Myotonic Dystrophy Type 1.

Myotonic Dystrophy Type 1 (DM1) is caused by elongation of a CTG repeat in the dystrophia myotonica protein kinase (DMPK) gene. mRNA transcripts containing the resulting CUGexp repeats form accumulations, or foci, in the nucleus of the cell. The pathogenesis of Myotonic dystrophy type 1 (DM1) is proposed to result from inappropriate patterns of alternative splicing caused by sequestration of the developmentally regulated alternative splicing factor muscleblind-like 1 (MBNL1), by these foci. Since eye lens cataract is a common feature of DM1 we have examined the distribution and dynamics of MBNL1 in lens epithelial cell lines derived from DM1 patients. The results demonstrate that only a small proportion of nuclear MBNL1 accumulates in CUGexp pre-mRNA foci. MBNL1 is, however, highly mobile and changes sub-cellular localization in response to altered transcription and splicing activity. Moreover, immunolocalization studies in lens sections suggest that a change in MBNL1 distribution is important during lens growth and differentiation. While these data suggest that loss of MBNL1 function due to accumulation in foci is an unlikely explanation for DM1 symptoms in the lens, they do demonstrate a strong relationship between sub-cellular MBNL1 localisation and pathways of cellular differentiation, providing an insight into the sensitivity of the lens to changes in MBNL1 distribution.

Source: BJ Cell - December 20, 2013 Category: Biochemistry Authors: S M Coleman, A R Prescott, J E Sleeman Tags: BJ Cell Source Type: research