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.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice
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
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)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
A gene-trapped vector was inserted into the mouse 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)
Description: Reduction in the level of Epo mRNA expression was shown in SENP1 homozygous null fetal livers; expression of EpoR, Jak2, STAT5, and growth factors c-kit and SCF was not significantly different between SENP1 homozygous null and wild-type fetal livers.
Description: No live SENP1 homozygous mice were found among offspring of SENP1 heterozygote intercrosses indicating that the SENP1 homozygous null mutation leads to embryonic lethality.
Description: SENP1 homozygous null embryos had severe fetal anemia and had more than 75% fewer erythrocytes and were paler and smaller than their wild-type or SENP1 heterozygous littermates.
Description: TUNEL-positive cells was much greater in the liver sections from SENP1 homozygous null embryos than in those of their wild-type littermates.
Description: Relative number of CFU-e arising from SENP1 homozygous null fetal liver was over 40% smaller than that from wild-type fetal liver; no significant difference in the numbers of the BFU-e between SENP1 homozygous null and wild-type fetal livers.
Description: Number of nucleated cells in the fetal livers of SENP1 homozygous null embryos was markedly decreased compared to their wild-type littermates; decrease in the number of erythropoietic foci in SENP1 heterozygous embryos compared with their wild-type littermates.
Description: Disruption of the SENP1 locus reduced deSUMOylation in SENP1 homozygous null embryos; SUMOylation pattern in lysates of embryos revealed an increase in high-molecular-weight SUMO-1 and SUMO-2/3 conjugates in SENP1 homozygous embryos in comparison with wild-type or SENP1 heterozygous null embryos.
Description: decreased mature spines and increased immature spines in layer II/III neurons of Senp1 haploinsufficient mice, indicating hindered spine development in the retrosplenial cortex
Exp Paradigm: injected AAV-CAG-FLEX-EGFP, AAV-hSyn-Cre
Description: brain width and thickness of the cerebral cortex significantly increased in both male and female Senp1 haploinsufficient mice
Exp Paradigm: width/height ratio
Description: numbers of inhibitory synapses were significantly increased in soma of retrospenial agranular cortex layer II/III neurons of Senp1 haploinsufficient mice; punctum co-labeled with VGAT and the a1 subunit of GABAA receptors were also increased in RSA layer II/III neurons of Senp1 haploinsufficient mice; inhibitory synaptic transmission of RSA layer II/III pyramidal neurons in Senp1 haploinsufficiency mice was increased likely due to more inhibitory synapses formed on these neurons
Exp Paradigm: injected AAV-CAG-FLEX-EGFP, AAV-hSyn-Cre to retrospenial agranular cortex; synapses measured by punctum co-labeled with vesicular GABA transporter and Gepyrin
Description: total spine numbers increased in the basal and apical dendrites of layer II/III and layer V neurons in Senp1 haploinsufficient mice
Exp Paradigm: injected AAV-CAG-FLEX-EGFP, AAV-hSyn-Cre
Description: GABAergic neurons, parvalbumin and somatostatin positive neurons, were specifically increased in the RSA cortex, specifically layer II/III and layer V of Senp1 haploinsufficient mice
Description: basal dendrites of layer II/III and layer V neurons exhibited less complexity; apical dendrites appeared to be more complex in Senp1 haploinsufficient mice suggesting that basal and apical dendrites were regulated differentially in vivo
Exp Paradigm: injected AAV-CAG-FLEX-EGFP, AAV-hSyn-Cre
Description: numbers of excitatory synapses were dramatically decreased in soma of RSA layer II/III neurons
Exp Paradigm: injected AAV-CAG-FLEX-EGFP, AAV-hSyn-Cre; punctum labeled by the co-staining of PSD95 and vesicular glutamate transporter 1 (VGlut1), as well as the co-staining of glutamate ionotropic receptor AMAP type subunit 2 (GRIA2) and VGlut1
Description: frequency of mIPSCs in retrosplenial agranular cortex layer II/III neurons of Senp1 haploinsufficient mice was significantly higher than that in WT mice
Exp Paradigm: recording on retrospenial agranular cortex layer II/III pyramidal neurons
Description: frequency, but not amplitude, of mEPSCs significantly decreased in Senp1 haploinsufficient mice
Exp Paradigm: recording on retrospenial agranular cortex layer II/III pyramidal neurons
Description: FMRP closely colocalized with SENP1 in the RSA neurons of the mouse brain and was downregulated in Senp1 haploinsufficient mice; FMRP was specifically downregulated in specific cortical regions, exclusing the hippocampus, in Senp1 haploinsufficient mice
Exp Paradigm: anti-SENP1 and anti-FMRP antibodies
Description: protein level of FMRP in the retrosplenial agranular cortex region was clearly downregulated in Senp1 haploinsufficient mice compared to that of WT mice
Exp Paradigm: tissue lysate collected from RSA region of Senp1 haploinsufficient and WT mice
Description: Senp1 was highly enriched in various cortical regions of the WT mouse brain and decreased in the brain of Senp1 haploinsufficient mice, downregulation most specific to the retrosplenial agranular cortex
Description: retrosplenial agranular cortex lysate from Senp1 haploinsufficient mice clearly showed an up-shifting band with FMRP positive signals, but not in WT mice, indicating that the FMRP-SUMO level increased; in vitro assay later confirmed suggestion that SENP1 is responsible to deSUMOylation of FMRP proteins
Exp Paradigm: anti-FMRP and anti-SUMO1
