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

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

  • J Clin Med. 2020 Jun 16;9(6):1886. doi: 10.3390/jcm9061886.
You-Kyung Lee 1,  Su-Kyeong Hwang 2,  Soo-Kyung Lee 1,  Jung-Eun Yang 3,  Ji-Hye Kwak 4,  Hyunhyo Seo 4,  Hyunjun Ahn 5 6,  Yong-Seok Lee 7,  Janghwan Kim 5 6,  Chae-Seok Lim 8,  Bong-Kiun Kaang 3,  Jae-Hyung Lee 9,  Jin-A Lee 1,  Kyungmin Lee 4
Affiliations

Affiliations

  • 1 Department of Biotechnology and Biological Sciences, Hannam University, Daejeon 34430, Korea.
  • 2 Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu 41944, Korea.
  • 3 Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.
  • 4 Laboratory for Behavioral Neural Circuitry and Physiology, Department of Anatomy, Brain Science & Engineering Institute, School of Medicine, Kyungpook National University, Daegu 41944, Korea.
  • 5 Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea.
  • 6 Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, 34113, Korea.
  • 7 Department of Physiology, Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
  • 8 Department of Pharmacology, Wonkwang University School of Medicine, Iksan 54538, Korea.
  • 9 Department of Life and Nanopharmaceutical Sciences, Department of Oral Microbiology, School of Dentistry, Kyung Hee University, Seoul 02447, Korea.
PMID: 32560273 DOI: 10.3390/jcm9061886
Abstract

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.

Keywords

Cohen syndrome; VPS13B; induced pluripotent stem cells (iPSCs); neurosphere; transcriptomic analysis.

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