A blueprint for research on Shankopathies: A view from research on autism spectrum disorder

Abstract

Autism spectrum disorders (ASD) are associated with mutations in a host of genes including a number that function in synaptic transmission. Phelan McDermid syndrome involves mutations in SHANK3 which encodes a protein that forms a scaffold for glutamate receptors at the synapse. SHANK3 is one of the genes that underpins the synaptic hypothesis for ASD. We discuss this hypothesis with a view to the broader context of ASD and with special emphasis on highly penetrant genetic disorders including Shankopathies. We propose a blueprint for near and longer-term goals for fundamental and translational research on Shankopathies.

Autism-associated SHANK3 haploinsufficiency causes I h channelopathy in human neurons

“…The symptoms resulting from impaired HCN-channels agree well with the hypothesized involvement of SHANK3 deletions in ASDs and Phelan-McDermid syndrome that are also commonly associated with intellectual disability, impaired learning and memory, and epilepsy (1-5). Therefore, our data collectively suggest that impairment of HCN-channel function may contribute to the manifestations of ASDs in patients with SHANK3 mutations and Phelan-McDermid syndrome.…”

“…Many mutations are thought to predispose to idiopathic ASDs by causing primary impairments in synaptic transmission (1-5). Our data show that SHANK3 haploinsufficiency impairs synaptic function, but also demonstrate that SHANK3 haploinsufficiency decreases I h -channel function as a primary impairment, which in turn produces major changes in intrinsic neuronal properties and secondarily affects synaptic function.…”

“…Haploinsufficiency of SHANK3 constitutes one of the more frequent single-gene mutations in autism spectrum disorders (ASDs; 1-5). Moreover, SHANK3 is among several genes deleted in Phelan-McDermid syndrome (a.k.a.…”

“…Moreover, SHANK3 is among several genes deleted in Phelan-McDermid syndrome (a.k.a. 22q13.3 deletion syndrome), and SHANK3 haploinsufficiency may be the most important contributing factor to Phelan-McDermid syndrome pathology (1-5). In addition, emerging evidence links SHANK3 mutations to schizophrenia (6,7), and SHANK3 overexpression has also been implicated in neuropsychiatric disorders (8).…”

Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders

“…; Sato et al . ; Carbonetto ). Indeed, SHANK3 haploinsufficiency is considered the major cause of neurological symptoms of Phelan‐McDermid syndrome (Phelan and McDermid ).…”