Relevance to Autism

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