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Relevance to Autism

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
ASD
Support
Evidence for 28 genetic disorders discovered by combining healthcare and research data
DD, ID
Support
Prevalence and architecture of de novo mutations in developmental disorders
DD, ID
Support
Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability
DD, ID
Recent Recommendation
De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders
DD, ID
ASD, ADHD, epilepsy/seizures, stereotypy
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1360R001 
 frameshift_variant 
 c.1964dup 
 p.Leu656SerfsTer3 
 De novo 
  
 Simplex 
 GEN1360R002 
 stop_gained 
 c.88C>T 
 p.Gln30Ter 
 De novo 
  
 Simplex 
 GEN1360R003 
 stop_gained 
 c.370C>T 
 p.Arg124Ter 
 De novo 
  
 Simplex 
 GEN1360R004 
 stop_gained 
 c.562G>T 
 p.Gly188Ter 
 De novo 
  
 Simplex 
 GEN1360R005 
 splice_site_variant 
 c.558G>A 
 p.Arg186%3D 
 De novo 
  
 Simplex 
 GEN1360R006 
 splice_region_variant 
 c.673dup 
 p.Thr225AsnfsTer5 
 De novo 
  
 Simplex 
 GEN1360R007 
 stop_gained 
 c.1714C>T 
 p.Gln572Ter 
 De novo 
  
 Simplex 
 GEN1360R008 
 stop_gained 
 c.1846C>T 
 p.Gln616Ter 
 De novo 
  
 Simplex 
 GEN1360R009 
 frameshift_variant 
 c.1965del 
 p.Lys655AsnfsTer23 
 De novo 
  
 Simplex 
 GEN1360R010 
 frameshift_variant 
 c.2158_2165del 
 p.Ser720AlafsTer15 
 De novo 
  
 Simplex 
 GEN1360R011 
 stop_gained 
 c.2724C>A 
 p.Phe908Leu 
 De novo 
  
 Simplex 
 GEN1360R012 
 splice_region_variant 
 c.3198+3A>G 
  
 De novo 
  
 Simplex 
 GEN1360R013 
 missense_variant 
 c.2432A>C 
 p.His811Pro 
 De novo 
  
  
 GEN1360R014 
 missense_variant 
 c.130G>T 
 p.Asp44Tyr 
 De novo 
  
  
 GEN1360R015 
 missense_variant 
 c.326A>T 
 p.Lys109Met 
 De novo 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
1
Duplication
 49
 
1
Duplication
 1
 
1
Deletion
 3
 
1
Duplication
 1
 

Model Summary

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
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Cortical thickness1
Decreased
 Immunohistochemistry
 E18.5
Cortical lamination1
Decreased
 Immunohistochemistry
 E18.5
Neuronal differentiation1
Decreased
 EdU incorporation
 E15.5
Cell proliferation: neural precursors1
Decreased
 EdU incorporation
 E15.5
Neocortex morphology: size1
Decreased
 Fluorescence microscopy
 E18.5
Brain size1
Decreased
 Macroscopic analysis
 E18.5
Stress granule function: neuronal1
Decreased
 Immunohistochemistry
 E18.5
Size/growth1
Decreased
 General observations
 unreported
Mortality/lethality: perinatal: incomplete penetrance1
Increased
 Genotypic ratio of progeny from heterozygous parents
 P1
Mortality/lethality: embryonic1
 No change
 Genotypic ratio of progeny from heterozygous parents
 E15.5, E18.5
 Not Reported:

 

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