Journal
CELL REPORTS
Volume 36, Issue 1, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109315
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Funding
- Young Investigator's Award grant from the Children's Tumor Foundation [2018-01-003]
- National Institutes of Health [1R35-NS07211-01]
- NCI Cancer Center Support Grant [P30CA091842]
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Neurodevelopmental disorders can be caused by chromosomal microdeletions involving numerous genes. This study identified abnormalities in neural stem cell proliferation and neuronal maturation in NF1-TGD patients, with reduced CRLF3 gene expression potentially contributing to these issues. Additionally, a deleterious germline mutation in the CRLF3 gene may lead to a higher autistic trait burden in NF1 patients.
Neurodevelopmental disorders are often caused by chromosomal microdeletions comprising numerous contiguous genes. A subset of neurofibromatosis type 1 (NF1) patients with severe developmental delays and intellectual disability harbors such a microdeletion event on chromosome 17q11.2, involving the NF1 gene and flanking regions (NF1 total gene deletion [NF1-TGD]). Using patient-derived human induced pluripotent stem cell (hiPSC)-forebrain cerebral organoids (hCOs), we identify both neural stem cell (NSC) proliferation and neuronal maturation abnormalities in NF1-TGD hCOs. While increased NSC proliferation results from decreased NF1/RAS regulation, the neuronal differentiation, survival, and maturation defects are caused by reduced cytokine receptor-like factor 3 (CRLF3) expression and impaired RhoA signaling. Furthermore, we demonstrate a higher autistic trait burden in NF1 patients harboring a deleterious germline mutation in the CRLF3 gene (c.1166T>C, p.Leu389Pro). Collectively, these findings identify a causative gene within the NF1-TGD locus responsible for hCO neuronal abnormalities and autism in children with NF1.
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