SHANK1 and autism spectrum disorders

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. autism spectrum disorders, SHANK1, synapse, genetics, mouse model Citation:Gong XH, Wang HY. Shank1 and autism spectrum disorders. Sci China Life Sci, 2015Sci, , 58: 985 -990, doi: 10.1007 Autism spectrum disorder (ASD) is a complex neurodevelopmental disease characterized by impaired social interaction and language development and repetitive and stereotyped behaviors and interests. ASD is more frequent in males than females, with an approximate ratio of 4 : 1 [1]. Twin and family studies indicate that genetic factors play an important role in the etiology of autism with the heritability estimate more than 90% [2,3]. Though the causes of ASD are largely unknown, neurexin-neuroligin-shank (NRXN-NLGN-SHANK) pathway genes mutations have been implicated in ASD [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. NLGN proteins, expressed highly in the brain, are postsynaptic adhesion molecules interacting with presynaptic NRXNs [9]. SHANK proteins function as core components of the postsynaptic density (PSD) by interacting with multiple proteins [21]. The impact of this pathway on synaptic function provides an important perspective for understanding the pathogenesis of ASD. The SHANK family has three members: SHANK1, SHANK2 and SHANK3. All SHANK family members are expressed in the brain and are present at PSD of excitatory synapses. SHANK3 was the first and one of the best characterized genes implicated in ASD in SHANK family [19,20]. Recently, deletions and point mutations of the SHANK1 gene have been detected in ASD individuals, indicating the involvement of SHANK1 in ASD [22]. This review focuses on the function of SHANK1 protein, Shank1 mouse models, and the molecular genetics of the SHANK1 gene in human ASD. The structure and function of SHANKproteinAll 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.

Phenotypic Subtyping and Re-Analysis of Existing Methylation Data from Autistic Probands in Simplex Families Reveal ASD Subtype-Associated Differentially Methylated Genes and Biological Functions

“…While PAX 6 is involved in modulating the fate of neural progenitor cells [ 37 ], genetic variants in PAX8 are associated with sleep disturbance [ 38 , 39 ], a frequent comorbidity of ASD. SHANK1 is a scaffolding protein at the postsynaptic density that has been found to be involved in ASD [ 40 ]. Mutations in CADM1 , which codes for a synaptic adhesion molecule, are also associated with ASD [ 41 ].…”

Solution structures of the SH3 domains from Shank scaffold proteins and their interactions with Cav1.3 calcium channels

“…Moreover, Shank proteins have also been implicated in Alzheimer's disease . Although the best characterized paralog is Shank3 , mutations in the Shank1 and Shank2 genes have also been reported to be associated with ASD . For example, the overexpression of Shank3 can cause manic‐like behavior in mice, suggesting that abnormalities in the copy number of Shank proteins can also induce certain psychiatric disorders .…”

Cataloguing and Selection of mRNAs Localized to Dendrites in Neurons and Regulated by RNA-Binding Proteins in RNA Granules

“…Shank1, Homer2, Dlg2, and Dlg4 are scaffold proteins of excitatory postsynaptic density. Shank1 regulates spine morphology and neurotransmission and is associated with ASD and neuropsychiatric disorders [156][157][158][159][160]. Homer2 interacts with dendritic spine actin regulators such as Cdc42 and drebrin, enhances cell surface expression of NMDA receptors, and is involved in spine maturation.…”