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Relevance to Autism

De novo loss-of-function variants in the PAX5 gene have been identified in two simplex ASD cases (Iossifov et al., 2014; O'Roak et al., 2014). A de novo likely damaging missense variant in PAX5 was identified in an ASD proband from the SPARK cohort (Feliciano et al., 2019); in the same report, a meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified PAX5 as an ASD candidate gene with a q-value 0.1.

Molecular Function

May play an important role in B-cell differentiation as well as neural development and spermatogenesis.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo gene disruptions in children on the autistic spectrum.
ASD
Support
Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.
ASD
Support
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
ASD
Support
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
ASD, DD
Support
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
ASD
Recent Recommendation
Delineation of a novel neurodevelopmental syndrome associated with PAX5 haploinsufficiency
ASD, DD, ID
ADHD, epilepsy/seizures
Recent Recommendation
Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes
ASD
Recent Recommendation
Low load for disruptive mutations in autism genes and their biased transmission.
ASD
Recent Recommendation
Recurrent de novo mutations implicate novel genes underlying simplex autism risk.
ASD
Recent Recommendation
Biallelic PAX5 mutations cause hypogammaglobulinemia
ASD
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN667R001 
 frameshift_variant 
 c.333del 
 p.Trp112GlyfsTer47 
 De novo 
  
 Simplex 
 GEN667R002 
 frameshift_variant 
 c.76dup 
 p.Val26GlyfsTer49 
 De novo 
  
 Simplex 
 GEN667R003 
 missense_variant 
 c.46G>C 
 p.Gly16Arg 
 De novo 
  
 Simplex 
 GEN667R004 
 missense_variant 
 c.385G>A 
 p.Val129Met 
 Familial 
 Maternal 
 Simplex 
 GEN667R005 
 missense_variant 
 c.338A>T 
 p.Glu113Val 
 De novo 
  
  
 GEN667R006 
 frameshift_variant 
 c.76dup 
 p.Val26GlyfsTer49 
 De novo 
  
 Simplex 
 GEN667R007 
 missense_variant 
 c.176G>A 
 p.Arg59Gln 
 Unknown 
  
  
 GEN667R008 
 missense_variant 
 c.1085G>A 
 XP_005251537.1:p.Gly362Glu 
 Unknown 
  
  
 GEN667R009 
 missense_variant 
 c.997G>A 
 XP_005251537.1:p.Gly333Arg 
 Unknown 
  
  
 GEN667R010 
 missense_variant 
 c.662G>A 
 p.Arg221Gln 
 Unknown 
  
  
 GEN667R011 
 missense_variant 
 c.868G>A 
 p.Gly290Arg 
 Unknown 
  
  
 GEN667R012 
 initiator_codon_variant 
 c.3G>A 
 p.Met1? 
 Unknown 
  
  
 GEN667R013 
 missense_variant 
 c.868G>A 
 p.Gly290Arg 
 Unknown 
  
  
 GEN667R014 
 missense_variant 
 c.868G>A 
 p.Gly290Arg 
 Unknown 
  
  
 GEN667R015 
 frameshift_variant 
 c.76dup 
 p.Val26GlyfsTer49 
 De novo 
  
 Simplex 
 GEN667R016 
 copy_number_loss 
  
  
 Unknown 
  
 Multiplex 
 GEN667R017 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN667R018 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN667R019 
 stop_gained 
 c.1129C>T 
 p.Arg377Ter 
 Unknown 
  
  
 GEN667R020 
 missense_variant 
 c.157G>C 
 p.Asp53His 
 Familial 
 Maternal 
 Multiplex 
 GEN667R021 
 missense_variant 
 c.419G>A 
 p.Arg140Gln 
 De novo 
  
  
 GEN667R022 
 missense_variant 
 c.661C>T 
 p.Arg221Trp 
 De novo 
  
  
 GEN667R023 
 missense_variant 
 c.962C>A 
 p.Pro321His 
 Unknown 
  
 Multiplex 
 GEN667R024a 
 missense_variant 
 c.92G>A 
 p.Arg31Gln 
 Familial 
 Maternal 
 Simplex 
 GEN667R024b 
 stop_gained 
 c.724G>T 
 p.Glu242Ter 
 De novo 
  
 Simplex 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
9
Deletion
 2
 
9
Duplication
 1
 
9
Duplication
 2
 
9
N/A
 1
 
9
Duplication
 7
 
9
Duplication
 3
 
9
Duplication
 1
 

Model Summary

Homozygous Pax5 mutant mice showed postnatal lethality where mutants became growth retarded in the second week and mostly died within 3 weeks (Urbánek, 1994). However, the authors reported that 11/200 HM mice survived the first 3 weeks and continued as underdeveloped animals for up to 7 months with accommodations such as delayed weaning and access to a second, surrogate nursing female. In a second study, conditional knockout models were generated by deleting Pax5 in GABAergic neurons (Ohtsuka, 2013). About 47% of conditional homozygous mutant mice and 19% of heterozygous mice developed hydrocephalus around postnatal day 50 and died approximately one to two weeks thereafter.

References

Type
Title
Author, Year
Additional
GABAergic neurons regulate lateral ventricular development via transcription factor Pax5
Primary
Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP
Model Type: Genetic
Model Genotype: Homozygous
Mutation: Cre-IRES-LacZ transgene was inserted at the first coding ATG of the Gad1 gene to achieve Cre-expression in GABAergic neurons. These mice were crossed with Pax5 floxed mice for Cre-mediated recombination of Pax5.
Allele Type: conditional knockout
Strain of Origin: CBA/C57 hybrid
Genetic Background: C57BL/6
ES Cell Line:
Mutant ES Cell Line:
Model Source: 11420047; 23349049
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Hyperactivity1
increased
 Open field test
 P 40-42
General locomotor activity1
decreased
 Home cage behavior
 P 40-42
Hydrocephaly1
increased
 General observations
 P 50
Size of cerebral ventricles: lateral ventricle1
increased
 Histology
 P 60
Mortality/lethality: life span: incomplete penetrance1
increased
 General observations
 P 58
Anxiety1
increased
 Open field test
 P 40-42
Size of cerebral ventricles: third ventricle1
 no change
 Histology
 P 60
 Not Reported:

 

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