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Cerebral organoids containing an AUTS2 missense variant model microcephaly

2022; Oxford University Press; Volume: 146; Issue: 1 Linguagem: Inglês

10.1093/brain/awac244

1460-2156

Summer Fair, Wesley N. Schwind, Dominic Julian, Alecia Biel, Gongbo Guo, Ryan Rutherford, Swetha Ramadesikan, Jesse J. Westfall, Katherine E. Miller, Meisam Naeimi Kararoudi, Scott E. Hickey, Theresa Mihalic Mosher, Kim L. McBride, Reid Neinast, James Fitch, Dean A. Lee, Peter White, Richard K. Wilson, Tracy A. Bedrosian, Daniel C. Koboldt, Mark E. Hester,

Epigenetics and DNA Methylation

Abstract Variants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain malformations. Here, we use a human cerebral organoid model to investigate the pathophysiology of a heterozygous de novo missense AUTS2 variant identified in a patient with multiple neurological impairments including primary microcephaly and profound intellectual disability. Proband cerebral organoids exhibit reduced growth, deficits in neural progenitor cell (NPC) proliferation and disrupted NPC polarity within ventricular zone-like regions compared to control cerebral organoids. We used CRISPR-Cas9-mediated gene editing to correct this variant and demonstrate rescue of impaired organoid growth and NPC proliferative deficits. Single-cell RNA sequencing revealed a marked reduction of G1/S transition gene expression and alterations in WNT-β-catenin signalling within proband NPCs, uncovering a novel role for AUTS2 in NPCs during human cortical development. Collectively, these results underscore the value of cerebral organoids to investigate molecular mechanisms underlying AUTS2 syndrome.