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Relevance to Autism

Whole-exome sequencing in a cohort of 168 Chinese ASD probands in Liu et al., 2022 identified two male probands with maternally-inherited variants in the SCGN gene; one of these variants was a missense variant (p.Arg79Trp) that was experimentally shown to fail to rescue neuronal morphology defects in scgn-deficient zebrafish. In the same report, deletion of Scgn in zebrafish or mice resulted in autism-like behaviors and impaired brain development, as well as disrupted oxytocin signalling and an abnormal activation in inflammation. A de novo loss-of-function variant in the SCGN gene was identified in a male ASD proband from a multiplex family from the MSSNG cohort (Zhou et al., 2022). Reduced plasma secretagogin (SCGN) levels had previously been reported in children with ASD compared to age- and gender-matched healthy controls in Alhowikan et al., 2017.

Molecular Function

he encoded protein is a secreted calcium-binding protein which is found in the cytoplasm. It is related to calbindin D-28K and calretinin. This protein is thought to be involved in KCL-stimulated calcium flux and cell proliferation.

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References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
ASD
DD
Support
Integrating de novo and inherited variants in 42
ASD
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1384R001 
 missense_variant 
 c.235C>T 
 p.Arg79Trp 
 Familial 
 Maternal 
  
 GEN1384R002 
 splice_site_variant 
 c.702+2T>G 
  
 Familial 
 Maternal 
  
 GEN1384R003 
 frameshift_variant 
 c.146del 
 p.Gly49ValfsTer7 
 De novo 
  
 Multiplex 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
6
Deletion
 1
 
6
Deletion
 1
 

Model Summary

Scgn homozygous mutant and knockdown models show a decrease in oxytocin signaling. The homozygous knockout mouse shows an increase in pro-inflammatory cytokines. The knockdown models shows ASD-like behavioral phenotypes, such as decrease in social memory and an increase in repetitive behaviors. Oxytocin treatment restores the behavioral phenotypes.

References

Type
Title
Author, Year
Model Type: Genetic
Model Genotype: Homozygous
Mutation: Scgn deficient animals were generated by multiple zygote injection of custom synthetic sgRNA and Cas9 mRNA, resulting in a knockout allele (Scgn^em1Ezb, MGI:6711490). Mice were generated on a C57BL/6 background and resulting progeny was characterized for potential targeting of the Scgn allele by PCR amplification of a 214 bp region flanking the site of sgRNA cleavage. Homozygous mice express a truncated transcript skipping exon 3 of the gene.
Allele Type: Knockout
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line:
Mutant ES Cell Line:
Model Source: UT Southwestern transgenic core, Ezra Burstein lab
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Neuronal number: oxytocin expressing1
Decreased
 RNA sequencing
 unreported
Microglial number1
Increased
 Immunohistochemistry
 unreported
Neurotransmitter release: neurohypophysial1
Decreased
 ELISA
 unreported
Cytokine levels: pro-inflammatory1
Increased
 ELISA
 unreported
Cytokine levels: pro-inflammatory1
Increased
 Quantitative PCR (qRT-PCR)
 unreported
Differential gene expression1
Abnormal
 RNA sequencing
 unreported
Metabolite levels: neurometabolites1
Abnormal
 Liquid chromatography-mass spectrometry (LC-MS)
 unreported
Hormone levels1
 No change
 ELISA
 unreported
 Not Reported:

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