Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Commun Biol. 2021 Nov 30;4(1):1342. doi: 10.1038/s42003-021-02845-0.
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.
Ⅰ型肌强直性营养不良（DM1）患者表现出广泛且多变的脑结构改变，其病因尚不清楚。我们证明了肌肉盲样蛋白 Mbnl1 和 Mbnl2 的失活会引发脑结构缺陷。4 月龄 Mbnl1/Mbnl2 小鼠的 2D FSE T2w MRI 显示全脑体积缩小、脑室扩大和区域性灰质和白质体积缩小。对 2 月龄 Mbnl1、Mbnl2 和 Mbnl1/Mbnl2 脑的比较 MRI 显示白质和灰质体积存在基因型特异性减少。在这两个队列中，白质体积减少占主导地位，Mbnl2 缺失导致的改变比 Mbnl1 缺失更为广泛。海马体积易受 Mbnl1 或 Mbnl2 水平变化的影响，单基因和双重缺失都会导致类似的体积损失。相比之下，皮质、间脑/中脑、小脑和后脑区域表现出基因和剂量特异性的体积减少。我们的研究结果为先天性 DM1 表型加重以及 DM1 中报道的脑结构改变的可变性提供了分子解释。
