SHANK3 Gene Mutations Associated with Autism Facilitate Ligand Binding to the Shank3 Ankyrin Repeat Region

Mameza, Marie Germaine; Dvoretskova, Elena; Bamann, Margarete; Hönck, Hans-Hinrich; Güler, Türkan; Boeckers, Tobias M.; Schoen, Michael; Verpelli, Chiara; Sala, Carlo; Barsukov, Igor; Dityatev, Alexander; Kreienkamp, Hans‐Jürgen

doi:10.1074/jbc.m112.424747

Cited by 50 publications

(96 citation statements)

References 39 publications

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“…To date, these de novo mutations have been studied in vitro using mutant Shank3 proteins that mimic the gene mutations. These studies provide evidence that mutated Shank3 proteins are either unable to be localized at synapses or regulate synapse morphology and function (Durand et al 2011;Verpelli et al 2011;Mameza et al 2013).…”

Section: Shanks: Structure Expression and Subcellular Localizationmentioning

confidence: 86%

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

Sala

Vicidomini

Bigi

et al. 2015

Journal of Neurochemistry

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Shank/ProSAP proteins are essential to synaptic formation, development, and function. Mutations in the family of SHANK genes are strongly associated with autism spectrum disorders (ASD) and other neurodevelopmental and neuropsychiatric disorders, such as intellectual disability (ID), and schizophrenia. Thus, the term 'Shankopathies' identifies a number of neuronal diseases caused by alteration of Shank protein expression leading to abnormal synaptic development. With this review we want to summarize the major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks and pave the way for the discovery of new therapeutic drugs targeted to treat patients with SHANK mutations and also patients affected by other neurodevelopmental and neuropsychiatric disorders.

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Section: Shanks: Structure Expression and Subcellular Localizationmentioning

confidence: 86%

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

Sala

Vicidomini

Bigi

et al. 2015

Journal of Neurochemistry

Self Cite

144

130

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“…The truncated SHANK3 also exerts a dominant-negative effect on spine induction and synaptic transmission (Arons et al, 2012; Durand et al, 2012). Another missense mutation (p.L68P) (Gauthier et al, 2009) located in the N-terminal domain does not compromise postsynaptic targeting or synaptic transmission, but enhances the interaction with cytoskeletal components (Mameza et al, 2013). …”

Section: The Shank Familymentioning

confidence: 99%

Phelan McDermid Syndrome

et al. 2015

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Phelan McDermid syndrome (PMS) or 22q13.3 deletion syndrome is a rare neurodevelopmental disorder characterized by generalized developmental delay, intellectual disability, absent or delayed speech, seizures, autism spectrum disorder, neonatal hypotonia, physical dysmorphic features, and recurrent medical comorbidities. In most cases, individuals with PMS have terminal deletions of the chromosomal region 22q13.3 encompassing SHANK3, a gene encoding a structural component of excitatory synapses indispensable for proper synaptogenesis and neuronal physiology. Here, we review the clinical aspects of the syndrome and the genetic findings shedding light onto the underlying etiology. We also provide an overview on the evidence from genetic studies and mouse models that supports SHANK3 haploinsufficiency as a major contributor of the neurobehavioral manifestations of PMS. Finally, we discuss how all these discoveries are uncovering the pathophysiology of PMS and are being translated into clinical trials for novel therapeutics ameliorating the core symptoms of the disorder.

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“…To date more than 14 point mutations, nucleotide insertions, microdeletions, microduplications, translocations, and chromosome deletions or rearrangements involving SHANK3 have been observed in genetic studies involving ASD patients [Bonaglia et al, 2001[Bonaglia et al, , 2006Durand et al, 2007;Gauthier et al, 2009Gauthier et al, , 2010Grabrucker, Schmeisser, Schoen, & Boeckers, 2011;Hamdan et al, 2011;Jiang & Ehlers, 2013;Kolevzon et al, 2011;Misceo et al, 2011;Moessner et al, 2007;Sykes et al, 2009]. Point mutations and deletions within Shank3 exons 4-9 have been shown to alter protein binding or to result in a complete loss of ankyrin repeat domain (ANK) function [Durand et al, 2007[Durand et al, , 2012; Mameza et al, 2013].…”

Section: Introductionmentioning

confidence: 99%

Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4‐9 Deletion Mouse Model of Autism

et al. 2015

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Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ~0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4–9, a region implicated in ASD patients. We find that homozygous deletion of exons 4–9 (Shank3e4–9 KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3e4–9 heterozygous (HET) and Shank3e4–9 KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3e4–9 KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3e4–9 KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3e4–9 HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3e4–9 KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3e4–9 mutant mouse model of autism.

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SHANK3 Gene Mutations Associated with Autism Facilitate Ligand Binding to the Shank3 Ankyrin Repeat Region

Cited by 50 publications

References 39 publications

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

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

Phelan McDermid Syndrome

Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4‐9 Deletion Mouse Model of Autism

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