Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, CH-1211 Geneva 4, Switzerland.
Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva 4, Switzerland.
Cells. 2020 Dec 3;9(12):2593. doi: 10.3390/cells9122593.
: Mucopolysaccharidosis type I-Hurler (MPS1-H) is a severe genetic lysosomal storage disorder due to loss-of-function mutations in the gene. The subsequent complete deficiency of alpha l-iduronidase enzyme is directly responsible of a progressive accumulation of glycosaminoglycans (GAG) in lysosomes which affects the functions of many tissues. Consequently, MPS1 is characterized by systemic symptoms (multiorgan dysfunction) including respiratory and cardiac dysfunctions, skeletal abnormalities and early fatal neurodegeneration. : To understand mechanisms underlying MPS1 neuropathology, we generated induced pluripotent stem cells (iPSC) from a MPS1-H patient with loss-of-function mutations in both alleles. To avoid variability due to different genetic background of iPSC, we established an isogenic control iPSC line by rescuing IDUA expression by a lentivectoral approach. : Marked differences between MPS1-H and -corrected isogenic controls were observed upon neural differentiation. A scratch assay revealed a strong migration defect of MPS1-H cells. Also, there was a massive impact of deficiency on gene expression (340 genes with an FDR <0.05). : Our results demonstrate a hitherto unknown connection between lysosomal degradation, gene expression and neural motility, which might account at least in part for the phenotype of MPS1-H patients.
黏多糖贮积症 I-H 型（MPS1-H）是一种严重的遗传性溶酶体贮积症，由于 基因的功能丧失性突变所致。随后，α-L-艾杜糖苷酸酶的完全缺乏直接导致糖胺聚糖（GAG）在溶酶体中进行性积累，从而影响许多组织的功能。因此，MPS1 的特征是全身症状（多器官功能障碍），包括呼吸和心脏功能障碍、骨骼异常和早期致命性神经退行性变。
为了了解 MPS1 神经病理学的机制，我们从一位 MPS1-H 患者中生成了诱导多能干细胞（iPSC），该患者的 基因的两个等位基因均存在功能丧失性突变。为了避免由于 iPSC 的不同遗传背景而导致的变异性，我们通过慢病毒载体方法拯救 IDUA 表达，建立了同基因对照 iPSC 系。
在神经分化过程中，观察到 MPS1-H 和 -校正同基因对照之间存在明显差异。划痕实验显示 MPS1-H 细胞的迁移缺陷明显。此外， 缺乏对基因表达也有巨大影响（FDR<0.05 的基因有 340 个）。
我们的研究结果表明，溶酶体降解、基因表达和神经运动之间存在着迄今未知的联系，这至少可以部分解释 MPS1-H 患者的表型。
