「偏見の遺伝子」が自閉症を解明する(’Gene of Prejudice’ Demystifies Autism)

2024-02-29

2024-02-28 カリフォルニア大学サンディエゴ校(UCSD)

ウィリアムズ症候群の人々は社交的で、一方で遺伝子の逆の変異を持つ人々は自閉症的な特徴を持ち、社会的に苦労する傾向があります。カリフォルニア大学サンディエゴ校の研究者は、GTF2I遺伝子の役割を明らかにし、これらの違いを理解しました。GTF2Iの欠失は脳の発達に影響を与え、社交性に重要な役割を果たす可能性があります。これは、自閉症スペクトラム障害の治療法の開発につながる可能性があります。

<関連情報>

GTF2Iの欠損は神経発達のヒト細胞モデルにおいて神経細胞のアポトーシスとシナプスの減少を促進する Loss of GTF2I promotes neuronal apoptosis and synaptic reduction in human cellular models of neurodevelopment

Jason W. Adams,Annabelle Vinokur,Janaína S. de Souza,…,Roberto H. Herai,Karl J. Wahlin,Alysson R. Muotri
Cell Reports Published:February 27, 2024
DOI:https://doi.org/10.1016/j.celrep.2024.113867

Highlights

•GTF2I-KO organoids show transcriptomic changes in synaptic function and apoptosis

•GTF2I-KO neural progenitors exhibit higher rates of proliferation

•GTF2I-KO neurons have decreased synaptic integrity and increased apoptosis

•GTF2I-KO organoids have fewer synaptic proteins and decreased electrical activity

Summary

Individuals with Williams syndrome (WS), a neurodevelopmental disorder caused by hemizygous loss of 26–28 genes at 7q11.23, characteristically portray a hypersocial phenotype. Copy-number variations and mutations in one of these genes, GTF2I, are associated with altered sociality and are proposed to underlie hypersociality in WS. However, the contribution of GTF2I to human neurodevelopment remains poorly understood. Here, human cellular models of neurodevelopment, including neural progenitors, neurons, and three-dimensional cortical organoids, are differentiated from CRISPR-Cas9-edited GTF2I-knockout (GTF2I-KO) pluripotent stem cells to investigate the role of GTF2I in human neurodevelopment. GTF2I-KO progenitors exhibit increased proliferation and cell-cycle alterations. Cortical organoids and neurons demonstrate increased cell death and synaptic dysregulation, including synaptic structural dysfunction and decreased electrophysiological activity on a multielectrode array. Our findings suggest that changes in synaptic circuit integrity may be a prominent mediator of the link between alterations in GTF2I and variation in the phenotypic expression of human sociality.