A de novo frameshift variant in the UBAP2L gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Jia et al., 2022 reported detailed genotypic and phenotypic information for a cohort of 12 individuals with de novo UBAP2L variants, including the ASD proband originally reported in Iossifov et al., 2014; all affected individuals presented with a neurodevelopmental disorder characterized by speech and language problems, intellectual disability, childhood motor delay/hypotonia, and various behavioral issues, including a formal diagnosis of autism spectrum disorder in 4 individuals. In the same report, the authors found that Ubap2l-haploinsufficient mice exhibited social and cognitive impairments accompanied by disrupted neurogenesis and reduced stress granule formation during early brain development. Lastly, enrichment analysis for de novo protein-altering variants in 40,853 probands with neurodevelopmental disorders, including 9,228 individuals with a primary diagnosis of ASD, in this report determined that UBAP2L showed an excess of de novo likely gene-disruptive (LGD) variants with a false discovery rate (FDR) less than or equal to 0.01.
Molecular Function
Enables RNA binding activity. Involved in binding activity of sperm to zona pellucida and stress granule assembly. Acts upstream of or within hematopoietic stem cell homeostasis. Part of PcG protein complex.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The contribution of de novo coding mutations to autism spectrum disorder
Deletion of Ubap2l resulted in increased perinatal mortality, with only 2.6% of surviving pups being homozygous, all of which were undersized. Haploinsufficiency of Ubap2l in mice led to decreased social memory with no social novelty preference. In addition, mice spent a greater amount of time in repetitive digging behavior, and displayed increased anxious behaviors. Heterozygous knockout embryos had normal neocortex morphology and brain size, whereas homozygous knockout embryos had decreased cortical length and area, and smaller brain size. Ubap2l knockout mutant embryos showed abnormal cortical lamination and decreased cortical thickness. Furthermore, Ubap2l KO led to decreased neurogenesis and intermediate progenitor cell proliferation, and decreased intensity and number of stress granules.
References
Type
Title
Author, Year
Primary
De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Ubap2l knockout was generated through CRISPR/Cas9 endonuclease-mediated deletion of exons 3 to 6.
Allele Type: Knockout
Strain of Origin: unreported
Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source: Cyagen Biosciences
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Ubap2l knockout was generated through CRISPR/Cas9 endonuclease-mediated deletion of exons 3 to 6.
Allele Type: Knockout
Strain of Origin: unreported
Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source: Cyagen Biosciences
Description: Homozygous Ubap2l knockout embryos displayed abnormal cortical lamination. Homozygous Ubap2l knockout embryos had reduced thickness and number of Satb2-positive cells compared to wildtype mice, however, no changes were observed in the density of Tbr1-positive and Ctip2-positive cells.
Exp Paradigm: Tbr1, Ctip2, Satb2
Description: Homozygous Ubap2l knockout embryos had a decreased ratio of EdU+ Pax6+ / Pax6+ cells compared to wildtype mice, indicating decreased neurogenesis.
Exp Paradigm: Pax6
Description: Homozygous Ubap2l knockout embryos showed a significant decrease in cortical length and cortical area compared to wildtype embryos.
Exp Paradigm: DAPI
Description: Homozygous Ubap2l knockout embryos had decreased thickness of the deeper-layer cortex labeled by deeper-layerâ??specific markers Tbr1 and Ctip2.
Exp Paradigm: Tbr1, Ctip2, Satb2
Description: Homozygous Ubap2l knockout embryos had significantly decreased intensity and number of stress granules (SGs) in mutant cortices compared to wildtype cortices. Homozygous Ubap2l knockout embryos displayed considerable TIA1-positive SGs in the developing cortex, indicating that there are stress events under normal physiological conditions. Homozygous Ubap2l knockout embryos had significantly increased intensity and number of stress granules in mutant cortices under arsenite stress (AS), compared to controls under AS.
Exp Paradigm: TIA1
Description: The ratio of surviving homozygous Ubap2l knockout mice is lower than expected Mendelian ratio compared to wildtype mice at P1, with only 2.6% of surviving pups being homozygous.
Genotypic ratio of progeny from heterozygous parents
Description: Heterozygous Ubap2l knockout embryos displayed abnormal cortical lamination. Heterozygous Ubap2l knockout embryos had reduced thickness and number of Satb2-positive cells compared to wildtype mice, however, no changes were observed in the density of Tbr1-positive and Ctip2-positivevcells.
Exp Paradigm: Tbr1, Ctip2, Satb2
Description: Heterozygous Ubap2l knockout embryos had a decreased ratio of EdU+ Pax6+ / Pax6+ cells compared to wildtype mice, indicating decreased neurogenesis.
Exp Paradigm: Pax6
Description: Heterozygous Ubap2l knockout embryos had decreased thickness of the deeper-layer cortex labeled by deeper-layerâ??specific markers Tbr1 and Ctip2.
Exp Paradigm: Tbr1, Ctip2, Satb2
Description: Heterozygous Ubap2l knockout embryos had significantly decreased intensity and number of stress granules (SGs) in mutant cortices compared to wildtype cortices. Heterozygous Ubap2l knockout embryos displayed considerable TIA1-positive SGs in the developing cortex, indicating that there are stress events under normal physiological conditions. Heterozygous Ubap2l knockout embryos had significantly decreased intensity and number of stress granules in mutant cortices under arsenite stress (AS), compared to controls under AS.
Exp Paradigm: TIA1
Description: Heterozygous Ubap2l knockout mice spent significantly less time interacting with the new stranger mouse and had no social preference index compared to wildtype mice.
