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:
Targeted deletion of exons 6 and 7 and a frame shift of Shank2 gene and treatment with 10mg/kg of 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB).
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: Increased locomotor activity indicative of hyperactivity measured as the distance traveled is refractory to cdppb treatment
Exp Paradigm: Open field test
Description: Decreased long term depression in scca1 synapses is restored to the same level as wild type
Exp Paradigm: Extracellular recordings after ltd inductions (low frequency stimulation (lfs)-ltd (1 hz, 900 pulses))
Description: Decreased long term potentiation in scca1 synapses is restored to the same level as wild type
Exp Paradigm: Extracellular recordings after ltp inductions (high frequency stimulation (hfs)-ltp (100 hz, 1 s), theta-burst stimulation (tbs)-ltp (10 trains of 4 pulses at 100 hz,delivered at an inter-train interval of 200 ms, repeated 4 times at 10 s interval)
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
Restored
Description: Nmda/ampa ratio is restored to the same level as wild type
Exp Paradigm: Whole-cell recording with voltage-clamped pyramidal neurons inca1
Description: No adverse effect in basal excitatory transmission such as input-output and paired-pulse ratio
Exp Paradigm: Extracellular recordings at hippocampal schaffer-collateral-ca1-pyramidal synapses
Description: Increased repetitive jumping behavior (mostly mixed with upright scrabbling) is refractory to cdppb treatment
Exp Paradigm: Observation of repetitive behavior in home cage
Description: Social interaction is restored to the same level as wild type
Exp Paradigm: Three-chambered social interaction assay between novel mouse and inanimate object
Description: No adverse effect in social novelty recognition as indicated by exploration of novel mouse
Exp Paradigm: Three-chambered social interaction assay between stranger mouse 1 and novel stranger mouse 2
Description: Increased anxiety (decreased time spent in open arms, increased time spent in closed arms, and increased number of closed, but not open, arm entries) is refractory to cdppb treatment
Exp Paradigm: Elevated plus maze test
Description: Nmdar associated signaling indicated by phosphorylation of glua1, camkiia/b, erk1/2, and p38 is restored to the same level as wild type
Exp Paradigm: Nmdar associated signaling
Description: Nmdar associated signaling indicated by phosphorylation of camkiia/b and p38 is restored to the same level as wild type
Exp Paradigm: Nmdar associated signaling
Description: Shank2 homozygous knockout mice show reduced motor coordination measured by an increased frequency of missteps, compared with wildtype mice. Exp Paradigm: Males only.
Description: Shank2 homozygous knockout mice show altered contact and alignment of the postsynaptic density with presynaptic axon terminals, and decreased density of excitatory synapses, compared to wild type controls. Exp Paradigm: Altered synaptic alignment was measured by number of free spines that were not in close contact with the presynaptic nerve terminals and number of mismatched excitatory synapses, in which the postsynaptic density was misaligned with the presynaptic nerve terminal.
Description: Decreased long-term depression (ltd) induced by low-frequency stimulation at sc-ca1 synapses Exp Paradigm: Extracellular recordings at hippocampal schaffer-collateral-ca1-pyramidal synapses of ltd induced by dhpg
Miniature post synaptic current frequency: excitatory2
Decreased
Description: Shank2 homozygous knockout mice show reduced frequency of mepsps compared to wild type control mice. Exp Paradigm: Males and females tested.
Description: Decreased social interaction demonstrated by decreased preference to explore novel mouse over inanimate object Exp Paradigm: Three-chambered social interaction assay between novel mouse and inanimate object
Description: Decreased ultrasonic vocalizations as indicated by longer latency and lower frequency of calls Exp Paradigm: Ultrasonic vocalization (usv) during interaction of male with novel female
Description: Increased anxiety shown by decreased time spent in open arms, increased time spent in closed arms, and increased number of closed, but not open, arm entries Exp Paradigm: Elevated plus maze test
Description: Decreased spatial learning as indicated by reduced amount of time in target quadrant and less frequency of crossing platform area Exp Paradigm: Morris water maze test
Description: Shank2 homozygous knockout mice show reductions in the levels of excitatory synaptic membrane proteins, including glud2, the nmda receptor subunit glun2c, and ampa receptor subunits (glua1 and glua2), compared to wild type control mice. Exp Paradigm: Crude synaptosomal and total synaptic proteins were measured. males and females tested.
Description: Shank2 homozygous knockout mice show no expression of shank2 protein in total cerebellar lysates or cerebellar shank2 localized at the molecular cell layer of the cerebellar cortex, at parallel fiber excitatory synapses or in the dendrites of purkinje cells as seen in wild type controls. Exp Paradigm: Calbindin was used to label purkinje cells. vglut1 and vgat were used as excitatory and inhibitory synaptic markers, respectively. males and females tested.-immunofluorescence staining
Description: Shank2 homozygous knockout mice show reductions in the levels of cytoplasmic proteins such as psd-95, psd-93, and homer, compared to wild type controls. Exp Paradigm: Males and females tested.
Description: Shank2 homozygous knockout mice show no expression of shank2 protein in total cerebellar lysates or cerebellar shank2 localized at the molecular cell layer of the cerebellar cortex, at parallel fiber excitatory synapses or in the dendrites of purkinje cells as seen in wild type controls. Exp Paradigm: Calbindin was used to label purkinje cells. vglut1 and vgat were used as excitatory and inhibitory synaptic markers, respectively. males and females tested.- western blot: cerebellum
Description: Shank2 homozygous knockout mice show reduced total levels of the cerebellar proteins, glud2, glua2, glua2/3, glun1, mglur1, psd93, homer, ip3r, camkiia/b, neurolignin1, vglut1, and cerebellar inhibitory synaptic proteins (gephyrin, vgat, and gad65) compared to wild type controls. Exp Paradigm: Males and females tested.
