Abstract
Myotonic Dystrophy Type I (DM1) patients demonstrate widespread and variable brain structural alterations whose etiology is unclear. We demonstrate that inactivation of the Muscleblind-like proteins, Mbnl1 and Mbnl2, initiates brain structural defects. 2D FSE T2w MRIs on 4-month-old Mbnl1+/−/Mbnl2−/− mice demonstrate whole-brain volume reductions, ventriculomegaly and regional gray and white matter volume reductions. Comparative MRIs on 2-month-old Mbnl1−/−, Mbnl2−/− and Mbnl1−/−/Mbnl2+/− brains show genotype-specific reductions in white and gray matter volumes. In both cohorts, white matter volume reductions predominate, with Mbnl2 loss leading to more widespread alterations than Mbnl1 loss. Hippocampal volumes are susceptible to changes in either Mbnl1 or Mbnl2 levels, where both single gene and dual depletions result in comparable volume losses. In contrast, the cortex, inter/midbrain, cerebellum and hindbrain regions show both gene and dose-specific volume decreases. Our results provide a molecular explanation for phenotype intensification in congenital DM1 and the variability in the brain structural alterations reported in DM1.
Highlights
Myotonic Dystrophy Type I (DM1) patients demonstrate widespread and variable brain structural alterations whose etiology is unclear
These montages demonstrated that the total number of slices were reduced by 1–4 slices with regional differences being observed in Mbnl1+/−/Mbnl2−/− brains when compared with Mbnl1+/+/Mbnl2+/+ brains (Fig. 1, Supplementary Figs. 3 and 4)
The results from this study support the hypothesis that CUGexpansion RNA- mediated stochastic losses in MBNL1 and MBNL2 are an important driver of the structural alterations reported in DM1 patient brains
Summary
Myotonic Dystrophy Type I (DM1) patients demonstrate widespread and variable brain structural alterations whose etiology is unclear. 2D FSE T2w MRIs on 4-month-old Mbnl1+/−/Mbnl2−/− mice demonstrate whole-brain volume reductions, ventriculomegaly and regional gray and white matter volume reductions. Comparative MRIs on 2-month-old Mbnl1−/−, Mbnl2−/− and Mbnl1−/−/Mbnl2+/− brains show genotypespecific reductions in white and gray matter volumes. In both cohorts, white matter volume reductions predominate, with Mbnl[2] loss leading to more widespread alterations than Mbnl[1] loss. CUG-expansion RNAs localize the SHARP transcription factor from the nucleus to the cytoplasm in patient myoblasts to alter steady-state mRNA levels[16] and repeatassociated non-AUG (RAN) translation can result in the generation of toxic peptides[17]. Additional sources of phenotypic variability are the stochastic CTG-repeat expansions that occur in somatic cells with time[3,21]
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