Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders

@article{Durand2007MutationsIT,
  title={Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders},
  author={Christelle M. Durand and Catalina Betancur and Tobias M. Boeckers and Juergen Bockmann and Pauline Chaste and Fabien Fauchereau and Gudrun Nygren and Maria R{\aa}stam and I. Carina Gillberg and Henrik Anckars{\"a}ter and Eili Sponheim and Hany Goubran-Botros and Richard Delorme and Nadia Chabane and Marie Christine Mouren-Sim{\'e}oni and Philippe de Mas and Eric Bieth and Bernadette Rog{\'e} and D{\'e}lphine Heron and Lydie Burglen and Christopher Gillberg and Marion Leboyer and Thomas Bourgeron},
  journal={Nature Genetics},
  year={2007},
  volume={39},
  pages={25-27}
}
SHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage–sensitive synaptic pathway that is involved in autism… 

SHANK proteins: roles at the synapse and in autism spectrum disorder

TLDR
An evaluation of human genetic data, as well as of in vitro and in vivo animal model data, may allow us to understand how disruption of SHANK scaffolding proteins affects the structure and function of neural circuits and alters behaviour.

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

TLDR
The major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks are summarized 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.

Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation

TLDR
Using microarrays, de novo copy number variations in the SHANK2 synaptic scaffolding gene in two unrelated individuals with autism-spectrum disorder (ASD) and mental retardation are identified, further link common genes between ASD and intellectual disability.

SHANK genes in autism: Defining therapeutic targets

Contribution of SHANK3 mutations to autism spectrum disorder.

TLDR
The combined data provide support that haploinsufficiency of SHANK3 can cause a monogenic form of autism in sufficient frequency to warrant consideration in clinical diagnostic testing.

SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism

TLDR
The functional effects of two de novo mutations (STOP and Q321R) and two inherited variations identified in patients with ASD strongly suggest that they could represent risk factors for ASD.

Cellular and synaptic network defects in autism

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

TLDR
Mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment and the clinical relevance of these genes remains to be ascertained.
...

References

SHOWING 1-10 OF 17 REFERENCES

Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism

Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These

A forkhead-domain gene is mutated in a severe speech and language disorder

TLDR
It is suggested that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is involved in the developmental process that culminates in speech and language.

Severe expressive-language delay related to duplication of the Williams-Beuren locus.

TLDR
The results suggest that specific genes at 7q11.23 are exquisitely sensitive to dosage alterations that can influence human language and visuospatial capabilities.

ProSAP/Shank proteins – a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease

TLDR
Interactions with receptors of the postsynaptic membrane including NMDA‐type and metabotropic glutamate receptors, and the actin‐based cytoskeleton suggest that ProSAP/Shanks may be important scaffolding molecules of thePSD with a crucial role in the assembly of the PSD during synaptogenesis, in synaptic plasticity and in the regulation of dendritic spine morphology.

Shank Expression Is Sufficient to Induce Functional Dendritic Spine Synapses in Aspiny Neurons

TLDR
It is reported that knock-down of Shank3/prolinerich synapse-associated protein-2 by RNA interference reduces spine density in hippocampal neurons and transgene expression of Shank 3 is sufficient to induce functional dendritic spines in aspiny cerebellar neurons, which strongly suggest that Shank proteins and the associated glutamate receptors participate in a concerted manner to form spines and functional synapses.

Spine architecture and synaptic plasticity

Genetics of austim: complex aetiology for a heterogeneous disorder

TLDR
The identification of chromosomal abnormalities and Mendelian syndromes among individuals with autism, in conjunction with data from genome screens and candidate-gene studies, has helped to refine the view of the complex genetics that underlies autism spectrum conditions.

Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome

TLDR
Three cases with a common breakpoint within SHANK3 share a number of common phenotypic features, such as mental retardation and developmental delay with severely delayed or absent expressive speech, and it is suggested that many similar cases may be overlooked.

Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum.

TLDR
Hypotonia and developmental delay are nonspecific findings observed in many malformation and genetic syndromes, however, in association with severe speech and language delay and autistic-like behavior, this phenotype may be a significant indication to consider the 22q13 deletion syndrome as a potential cause.