Rare SHANK2 deletions have been identified in ASD cases, but not in controls (PMIDs 20473310, 20531469, 22346768); all SHANK2 deletions were de novo in origin and were predicted to disrupt coding exons , although a meta-analysis failed to reach statistical significance (P=0.076) (PMID 25188300). De novo LoF variants in SHANK2 have been identified in simplex ASD cases that were not observed in controls (PMIDs 20473310, 22495306, 31981491). Rare coding-sequence variants in SHANK2 affecting conserved amino acids/predicted to be damaging have been shown to be statistically enriched in ASD cases vs. controls (PMIDs 22346768, 25188300); many of these variants have been found to have functional consequences in neuronal cell cultures (PMIDs 21994763, 22346768). Mice deficient in SHANK2 exhibit hyperactivity and autistic behaviors, such repetitive grooming and abnormalities in vocal and social behavior (PMID 22699619). Integrated Transmission and De Novo Association (TADA) analysis of small de novo deletions and exome mutations from the Simons Simplex Collection, the Autism Sequencing Consortium, and the Autism Genome Project identified SHANK2 as a ASD risk gene with a false discovery rate (FDR) 0.01 (Sanders et al., 2015); a false discovery rate (FDR) 0.01 for SHANK2 was replicated following TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020. Analysis of cortical neurons from induced pluripotent stem cells derived from two ASD probands with de novo mutations in SHANK2 that were originally reported in Berkel et al., 2010 demonstrated increases in dendritic length and complexity, synapse number, and frequency of spontaneous excitatory postsynaptic currents compared to controls (Zaslavsky et al., 2019). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified SHANK2 as a gene reaching exome-wide significance (P < 2.5E-06). Hassani Nia et al., 2022 described a 17-year-old German male with a de novo missense variant in the SHANK2 gene (NM_012309.5:c.1927G>C;p.Gly643Arg) who presented with autism spectrum disorder, intellectual disability, and epilepsy; functional assessment demonstrated that this variant reduced post-synaptic targeting of Shank2 in primary cultured neurons, altered glutamatergic synaptic transmission, and interfered with the formation of post-synaptic clusters.
Molecular Function
Shank proteins contain multiple domains for protein-protein interactions and function as molecular scaffolds in the postsynaptic density (PSD).
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation.
134 Chinese male ASD probands and a control cohort of 232 typically developing Chinese boys and 256 pseudo-controls constructed from genotyping data from 256 family trios
298 Chinese male ADHD probands and a control cohort of 232 typically developing Chinese boys and 256 pseudo-controls constructed from genotyping data from 256 family trios
298 Chinese male ADHD probands and a control cohort of 232 typically developing Chinese boys and 256 pseudo-controls constructed from genotyping data from 256 family trios
298 Chinese male ADHD probands and a control cohort of 232 typically developing Chinese boys and 256 pseudo-controls constructed from genotyping data from 256 family trios
298 Chinese male ADHD probands and a control cohort of 232 typically developing Chinese boys and 256 pseudo-controls constructed from genotyping data from 256 family trios
Rescue Type:
RESCUE-Pharmaceutical
Rescue Paradigm:
Allosteric modulation of the GABA-A receptor using L838,417 (0.1 mg/kg, i.p. injection, 30 mins before behavioral testing at 1.8-3.5 months) in Shank2 KO mice with deleted exon 7 on a mixed background of 75 % C57Bl/6J and 25 % C57Bl/6N.
Treatment does not improve measured phenotype (was expected to do so)
Ameliorated
Treatment provides partial correction or improvement of measured phenotype
No adverse effect
Treatment does not affect the parameter adversely
Sustained effect
Treatment has long term effect of restoration or amelioration, tested AFTER stopping administration (not applied for continuing long-term treatment) . Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
No sustained effect
Treatment has no long term of restoration or amelioration detectable, after stopping administration. Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
Description: L838417 treated shank2 exon 7 ko mice show no difference in swimming velocity compared to untreated shank2 exon 7 ko mice.
Exp Paradigm: Morris water maze task included 6 training days and 1 day of probe trial test.
Description: L838417 treated shank2 exon 7 ko mice show no change in latency to find the platform during training sessions compared to untreated shank2 exon 7 ko mice.
Exp Paradigm: Probe tests were performed as training trials with no platform and the mice were tracked for 60s.
Description: L838417 treated shank2 exon 7 ko mice show restored spatial reference memory measured by the reduced mean distance from the platform during probe test on day 7 and more time spent in the target quadrant than in the other quadrants, compared to untreated shank2 exon 7 ko mice.
Exp Paradigm: Probe tests were performed as training trials with no platform and the mice were tracked for 60s.
Description: Shank2 exon 7 ko mice showed a significant deficit in spatial learning during training sessions compared to wildtype controls. Exp Paradigm: Learning curve during 6 days of training in the morris water maze task plotted latency for mice to reach the platform.
Description: Shank2 exon 7 ko mice show decreased ability to find the removed platform during probe trial by swimming randomly whereas wt control mice spend more time in the target quadrant. Exp Paradigm: Learning curve during 6 days of training in the morris water maze task plotted latency for mice to reach the platform. probe tests were performed as training trials with no platform and the mice were tracked for 60s.
Description: Shank2 exon 6-7 ko mice show increased transcription of gria1 and dlg4 compared to wildtype controls. Exp Paradigm: Total rna was extracted in trizol. raw sequence data were mapped onto the mouse genome reference mm10 using gsnap. cufflinks package was used to identify differentially expressed genes (degs, greater than 1.5 fold difference). to assess expression levels of genes, the rpkm (reads per kilobase of exon per million mapped reads) measure was calculated. panther and go were used to classify degs into functional protein classes. gapdh internal control was used in qrt-pcr.-rna sequencing: hippocampus
Description: Shank2 exon 6-7 ko mice show increased transcription of gria1 and dlg4 compared to wildtype controls. Exp Paradigm: Total rna was extracted in trizol. raw sequence data were mapped onto the mouse genome reference mm10 using gsnap. cufflinks package was used to identify differentially expressed genes (degs, greater than 1.5 fold difference). to assess expression levels of genes, the rpkm (reads per kilobase of exon per million mapped reads) measure was calculated. panther and go were used to classify degs into functional protein classes. gapdh internal control was used in qrt-pcr.- quantitative pcr (qrt-pcr)
