Relevance to Autism

Recurrent mutations in the SHANK3 gene have been identified in multiple individuals with ASD as described below. SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). 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 SHANK3 as a gene reaching exome-wide significance (P < 2.5E-06). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232).

Molecular Function

Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation.

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Model Summary

Knockout of shank3b results in a number of developmental and behavioral deficits. During early larval development (1-7 days post fertilization), shank3b-mutant zebrafish show increased lethality, abnormal morphological changes (tail bending, reduction of melanin content in eye), decrease in locomotor activity, and decreased startle response. Adult shank3b-mutant zebrafish continue to exhibit deficits in locomotor behavior, as well as show increased repetitive behaviors, decreased shoaling behavior as well as decreased kin preference. Moreover, they show decreased levels of proteins homer1 and synaptophysin, indicating persistent changes in synaptic function.

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