Abstract
Autism spectrum disorders (ASD) are highly heterogeneous pediatric developmental disorders with estimated heritability more than 70%. Although the genetic factors in ASD are mainly unknown, a large number of gene mutations have been found, especially in genes involved in neurogenesis. The Neurexin-Neuroligin-Shank (NRXN-NLGN-SHANK) pathway plays a key role in the formation, maturation and maintenance of synapses, consistent with the hypothesis of neurodevelopmental abnormality in ASD. Presynaptic NRXNs interact with postsynaptic NLGNs in excitatory glutamatergic synapses. SHANK proteins function as core components of the postsynaptic density (PSD) by interacting with multiple proteins. Recently, deletions and point mutations of the SHANK1 gene have been detected in ASD individuals, indicating the involvement of SHANK1 in ASD. This review focuses on the function of SHANK1 protein, Shank1 mouse models, and the molecular genetics of the SHANK1 gene in human ASD.
Highlights
MOE Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China
The Neurexin-Neuroligin-Shank (NRXN-NLGN-SHANK) pathway plays a key role in the formation, maturation and maintenance of synapses, consistent with the hypothesis of neurodevelopmental abnormality in Autism spectrum disorders (ASD)
SHANK proteins function as core components of the postsynaptic density (PSD) by interacting with multiple proteins
Summary
All three SHANK proteins have similar sets of domains: N-terminal multiple ankyrin repeats, a Src homology 3 (SH3) domain, a PSD-95/Discs large/ZO-1 (PDZ) domain, a long proline-rich region containing homer- and cortactin-binding sites, and a sterile alpha motif (SAM) domain. Through these multiple domains, SHANK family proteins interact with more than 30 synaptic proteins, consistent with the function of scaffolding proteins [23]. SHANK family members may play different roles in synaptogenesis and synapse maturation Their levels at the PSD are tightly regulated via Zn2+ ions in an isoform-specific way [39]. Promoter-associated CpG islands of all SHANK members were always completely unmethylated
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