Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes

Journal of Clinical Medicine

Bong-Kiun Kaang¹  Jung-eun Yang¹  Soo-Kyung Lee²  Jin-A Lee²  You-Kyung Lee²  Jae-Hyung Lee³  Su-Kyeong Hwang⁴  Chae-Seok Lim⁵  Yong-Seok Lee⁶  Ji-Hye Kwak⁷  Hyunhyo Seo⁷  Kyungmin Lee⁷  Janghwan Kim⁸  Hyunjun Ahn⁸ 

[1] Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea;Department of Biotechnology and Biological Sciences, Hannam University, Daejeon 34430, Korea;Department of Life and Nanopharmaceutical Sciences, Department of Oral Microbiology, School of Dentistry, Kyung Hee University, Seoul 02447, Korea;Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu 41944, Korea;Department of Pharmacology, Wonkwang University School of Medicine, Iksan 54538, Korea;Department of Physiology, Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea;Laboratory for Behavioral Neural Circuitry and Physiology, Department of Anatomy, Brain Science & Engineering Institute, School of Medicine, Kyungpook National University, Daegu 41944, Korea;Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea;

关键词: Cohen syndrome;    VPS13B;    induced pluripotent stem cells (iPSCs);    neurosphere;    transcriptomic analysis;   

DOI  :  10.3390/jcm9061886

来源: DOAJ

【 摘 要 】

Cohen syndrome (CS), a rare autosomal recessive disorder, has been associated with genetic mutations in the VPS13B gene, which regulates vesicle-mediated protein sorting and transport. However, the cellular mechanism underlying CS pathogenesis in patient-derived human neurons remains unknown. We identified a novel compound heterozygous mutation, due to homozygous variation of biparental origin and heterozygous variation inherited from the father, in the VPS13B gene in a 20-month-old female patient. To understand the cellular pathogenic mechanisms, we generated induced pluripotent stem cells (iPSCs) from the fibroblasts of the CS patient. The iPSCs were differentiated into forebrain-like functional glutamatergic neurons or neurospheres. Functional annotation from transcriptomic analysis using CS iPSC-derived neurons revealed that synapse-related functions were enriched among the upregulated and downregulated genes in the CS neurons, whereas processes associated with neurodevelopment were enriched in the downregulated genes. The developing CS neurospheres were small in size compared to control neurospheres, likely due to the reduced proliferation of SOX2-positive neural stem cells. Moreover, the number of SV2B-positive puncta and spine-like structures was significantly reduced in the CS neurons, suggesting synaptic dysfunction. Taking these findings together, for the first time, we report a potential cellular pathogenic mechanism which reveals the alteration of neurodevelopment-related genes and the dysregulation of synaptic function in the human induced neurons differentiated from iPSCs and neurospheres of a CS patient.

【 授权许可】

Unknown