TY - JOUR
KW - AUTS2 syndrome
KW - Autistic Disorder
KW - CRISPR-Cas9
KW - Cytoskeletal Proteins
KW - Humans
KW - Intellectual Disability
KW - Microcephaly
KW - Neural Stem Cells
KW - organoids
KW - Transcription Factors
KW - cerebral organoids
KW - Microcephaly
KW - neurodevelopmental disorder
AU - Summer R. Fair
AU - Wesley Schwind
AU - Dominic L. Julian
AU - Alecia Biel
AU - Gongbo Guo
AU - Ryan Rutherford
AU - Swetha Ramadesikan
AU - Jesse Westfall
AU - Katherine E. Miller
AU - Meisam Naeimi Kararoudi
AU - Scott E. Hickey
AU - Theresa Mihalic Mosher
AU - Kim L. McBride
AU - Reid Neinast
AU - James Fitch
AU - Dean A. Lee
AU - Peter White
AU - Richard K. Wilson
AU - Tracy A. Bedrosian
AU - Daniel C. Koboldt
AU - Mark E. Hester
AB - 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.
BT - Brain: A Journal of Neurology
DA - 2023-01-05
DO - 10.1093/brain/awac244
IS - 1
LA - eng
N2 - 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.
PY - 2023
SP - 387
EP - 404
T2 - Brain: A Journal of Neurology
TI - Cerebral organoids containing an AUTS2 missense variant model microcephaly
VL - 146
SN - 1460-2156
ER -