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.
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.
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
Model Type:
Genetic
Model Genotype:
Wildtype
Mutation:
The shRNA was applied to knockdown Scgn. Designed AAV delivers shRNA targeting mouse Scgn or shControl-GFP. Mice were anesthetized with isoflurane and then fastened to the stereotaxic device. shControl and shScgn AAVs were injected into the hypothalamus paraventricular nucleus (PVN) bilateral through an automatic microinjection instrument.
Allele Type: Knockdown
Strain of Origin: Unreported
Genetic Background: Unreported
ES Cell Line: Mutant ES Cell Line: Model Source: Beijing Syngentech Co., LTD
Description: Scgn knockout mice exhibited a more dense distribution and greater number of IBA1+ microglia in the paraventricular nucleus relative to that of Scgn wildtype mice.
Exp Paradigm: IBA1
Description: The hypothalamus of Scgn knockout mice exhibited decreased expression of many genes in the oxytocin pathway, such as Oxt, Ppp3cb, and Plcb3, compared to wildtype mice.
Exp Paradigm: Oxt
Description: The serum of Scgn knockout mice exhibited a decrease in levels of oxytocin by approximately 30% compared to age-matched wildtype mice.
Exp Paradigm: Oxytocin
Description: The hypothalamus of Scgn knockout mice exhibited up-regulated levels of critical pro-inflammatory genes, including IL-6 and TNF, compared to wildtype mice.
Exp Paradigm: IL-6, TNF
Description: The serum metabolome of Scgn knockout mice displayed disrupted oxytocin signaling and the neuroactive ligand-receptor interaction pathway relative to wildtype controls.
Exp Paradigm: LC-ESI-MS/MS system
Description: The hypothalamus of Scgn knockout mice exhibited an abnormal gene expression profile, with changes in pathways such as neurotransmitter receptor activity as well as multiple immune regulatory pathways, including inflammatory and innate immune response.
Description: shScgn mice displayed a reduction of more than half of the plasma oxytocin levels in the paraventricular nucleus compared to shControl mice.
Exp Paradigm: Oxytocin
Description: shScgn mice spent more time self-grooming than shControl mice, as shown by an average of 100 s for shScgn mice and 40 s for shControl mice.
Description: shControl mice spent 52% of their time exploring the S2 stranger and relatively more time sniffing S2 compared to shScgn mice, which spent 30% of the time with S2 and relatively less time sniffing S2. Overall, shScgn displayed a reversed preference index in both chamber and sniffing time, preferring the S1 familiar mouse over the S2 stranger.
