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Relevance to Autism

Whole-exome sequencing of over 700 Chinese ASD probands in Yang et al., 2021 identified a de novo nonsense variant in the SENP1 gene in a male ASD proband who exhibited typical deficits in social behaviors including communication and interaction (as measured by ADOS and CARS scores) but a largely normal Developmental Quotient (as measured by the Gesell development scale); in the same report, Senp1 +/- mice were found to exhibit core autistic-like symptoms, such as social deficits and repetitive behaviors, but normal learning and memory ability. A rare de novo splice-region variant in SENP1 had previously been observed in an ASD proband from the Autism Sequencing Consortium (Satterstrom et al., 2020).

Molecular Function

This gene encodes a cysteine protease that specifically targets members of the small ubiquitin-like modifier (SUMO) protein family. This protease regulates SUMO pathways by deconjugating sumoylated proteins. This protease also functions to process the precursor SUMO proteins into their mature form.

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References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice
ASD
Support
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
ASD
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1296R001 
 stop_gained 
 c.151C>T 
 p.Gln51Ter 
 De novo 
  
  
 GEN1296R002 
 splice_region_variant 
 c.-44-4A>G 
  
 De novo 
  
  
 GEN1296R003 
 stop_gained 
 c.151C>T 
 p.Gln51Ter 
 De novo 
  
 Simplex 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
12
Duplication
 1
 

Model Summary

Heterozygous knockout models of Senp1 showed ASD-related core behavioral features such as social deficits and elevated repetitive behaviors in multiple experimental paradigms. However, mutant mice showed normal learning and memory abilities compared to wild type. Several phenotypes related to brain development and function were compromised in the Snp1 haploinsufficient mice.

References

Type
Title
Author, Year
Primary
SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia
Primary
SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice
Model Type: Genetic
Model Genotype: Homozygous
Mutation: A gene-trapped vector was inserted into intron 8 of the Senp1 locus at codon 310 to generate a truncated SENP1 (1-309)-beta-galactosidase fusion protein lacking the C-terminal catalytic domain of SENP1.
Allele Type: knockout
Strain of Origin:
Genetic Background: C57BL/6
ES Cell Line: XG001
Mutant ES Cell Line:
Model Source: Jinke Cheng Lab (PMID 17981124)
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Gene expression 1
Decreased
 Quantitative PCR (qRT-PCR)
 E11.5
Mortality/lethality: embryonic1
Increased
 General observations
 E13-E15
Cardiovascular development and function1
Decreased
 Histology
 E15.5
Apoptosis1
Increased
 Cell survival analysis
 E13.5
Cell differentiation: hematopoiesis1
Decreased
 Flow cytometric analysis
 E13.5
Targeted expression1
Decreased
 Quantitative PCR (qRT-PCR)
 E10.5, E11.5
Cell differentiation: hematopoiesis1
Decreased
 Histology
 E13.5
Protein modification process1
Increased
 Western blot
 E10.5, E11.5
Apoptosis1
Increased
 TUNEL assay
 E13.5
Protein expression: in situ protein expression1
Decreased
 Immunohistochemistry
 E12.5
Cell proliferation1
 No change
 Immunohistochemistry
 E13.5
 Not Reported:

 

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