A common single nucleotide variant in the cytokine receptor-like factor-3 (CRLF3) gene causes neuronal deficits in human and mouse cells

Author:

Wilson Anna F1,Barakat Rasha1,Mu Rui1,Karush Leah L1,Gao Yunqing1,Hartigan Kelly A1,Chen Ji-Kang1,Shu Hongjin2,Turner Tychele N34,Maloney Susan E24,Mennerick Steven J2,Gutmann David H1,Anastasaki Corina1

Affiliation:

1. Department of Neurology, Washington University School of Medicine , Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110 , United States

2. Department of Psychiatry, Washington University School of Medicine , Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110 , United States

3. Department of Genetics, Washington University School of Medicine , Box 8232, 660 South Euclid Avenue, St. Louis, MO 63110 , United States

4. Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine , Box 8504, 660 South Euclid Avenue, St. Louis, MO 63110 , United States

Abstract

Abstract Single nucleotide variants in the general population are common genomic alterations, where the majority are presumed to be silent polymorphisms without known clinical significance. Using human induced pluripotent stem cell (hiPSC) cerebral organoid modeling of the 1.4 megabase Neurofibromatosis type 1 (NF1) deletion syndrome, we previously discovered that the cytokine receptor-like factor-3 (CRLF3) gene, which is co-deleted with the NF1 gene, functions as a major regulator of neuronal maturation. Moreover, children with NF1 and the CRLF3L389P variant have greater autism burden, suggesting that this gene might be important for neurologic function. To explore the functional consequences of this variant, we generated CRLF3L389P-mutant hiPSC lines and Crlf3L389P-mutant genetically engineered mice. While this variant does not impair protein expression, brain structure, or mouse behavior, CRLF3L389P-mutant human cerebral organoids and mouse brains exhibit impaired neuronal maturation and dendrite formation. In addition, Crlf3L389P-mutant mouse neurons have reduced dendrite lengths and branching, without any axonal deficits. Moreover, Crlf3L389P-mutant mouse hippocampal neurons have decreased firing rates and synaptic current amplitudes relative to wild type controls. Taken together, these findings establish the CRLF3L389P variant as functionally deleterious and suggest that it may be a neurodevelopmental disease modifier.

Funder

National Institute of Neurological Disorders and Stroke

Washingt on University Institute of Clinical and Translational Sciences

National Cancer Institute

Taylor Institute for Innovative Psychiatric Research

National Institute of Mental Health

Intellectual and Developmental Disabilities Research Center

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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