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.
Highlights
Cohen syndrome (CS) is a rare autosomal recessive disorder characterized by intellectual disability, postnatal microcephaly, facial dysmorphism, and/or motor abnormalities, with significant variability in the spectrum of its clinical features [1,2]
Homozygous or compound heterozygous mutations in VPS13B are identified in most CS patients, only one heterozygous mutation is detected in about 20%–30% of patients, whereas no mutations are identified in 12% of patients, indicating that other genetic mutations and environmental factors are related to CS pathogenesis [8]
Cohen syndrome (CS) is an uncommon autosomal recessive developmental disorder that has been attributed to mutations in the VPS13B gene in patients of diverse genetic backgrounds [2]
Summary
Cohen syndrome (CS) is a rare autosomal recessive disorder characterized by intellectual disability, postnatal microcephaly, facial dysmorphism, and/or motor abnormalities, with significant variability in the spectrum of its clinical features [1,2]. Homozygous or compound heterozygous mutations in VPS13B are identified in most CS patients, only one heterozygous mutation is detected in about 20%–30% of patients, whereas no mutations are identified in 12% of patients, indicating that other genetic mutations and environmental factors are related to CS pathogenesis [8]. For these complex cases, the underlying cellar mechanism that causes each case of CS remains largely unknown
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