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

Department of Molecular Human Genetics, Ruprecht-Karls-University, Heidelberg, Germany.
Nature Genetics (Impact Factor: 29.35). 05/2010; 42(6):489-491. DOI: 10.1038/ng.589
Source: PubMed


Using microarrays, we identified de novo copy number variations in the SHANK2 synaptic scaffolding gene in two unrelated individuals with autism-spectrum disorder (ASD) and mental retardation. DNA sequencing of SHANK2 in 396 individuals with ASD, 184 individuals with mental retardation and 659 unaffected individuals (controls) revealed additional variants that were specific to ASD and mental retardation cases, including a de novo nonsense mutation and seven rare inherited changes. Our findings further link common genes between ASD and intellectual disability.

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    • ") and (3) several mutations in SHANK2 including a 120 kb deletion selectively disrupting exon 7 had been identified in unrelated human individuals with ASD and/or mental retardation (Berkel et al., 2010). "
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    ABSTRACT: The Shank family comprises three core postsynaptic scaffold proteins of excitatory synapses in the mammalian brain: Shank1, Shank2 and Shank3. Since mutations in all three human SHANK genes are linked to neuropsychiatric disorders such as autism and schizophrenia, Shank mutant mice serve as corresponding in vivo model systems. Besides intriguing alterations in behavior, dysfunction of glutamatergic synapses has emerged as a pathological hallmark among several Shank mutant lines. However, there is very limited knowledge of the underlying pathomechanisms. Therefore, precise neurobiological evaluation of morphological, molecular and electrophysiological phenotypes in Shank mutants is crucially needed. In this brief review, I will focus on the Shank mutant mouse lines we have generated so far and discuss how they might help us to develop translational treatment studies in the future. Copyright © 2015 Elsevier GmbH. All rights reserved.
    Annals of Anatomy - Anatomischer Anzeiger 04/2015; 200:115-117. DOI:10.1016/j.aanat.2015.03.006 · 1.48 Impact Factor
    • "In addition , 744,000 copy-number probes were added that were evenly spaced along the genome to enable higher-resolution breakpoint mapping. This microarray is still used (Berkel et al., 2010; Ramachandran et al., 2014). Subsequently, the CytoScan series of microarrays were launched by Affymetrix. "
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    ABSTRACT: Diagnosing constitutional pathogenic copy number variants (CNVs) requires detecting submicroscopic segmental chromosomal imbalances. The Affymetrix GeneChip mapping array was one of the initial microarray platforms used to measure duplication and deletion of genetic material in DNA samples. Unlike oligonucleotide microarrays from NimbleGen and Agilent, developed around the same time to infer copy number status for the DNA sequence covered by the probe, the Affymetrix GeneChip system used 25-mer oligonucleotide probes designed to interrogate SNPs. Thus, it was possible to use the Affymetrix 'SNP chips' to both identify SNPs and to identify copy number status. Affymetrix now offers the CytoScan microarray platforms, which are optimized for copy-number analyses, and provides accompanying software. They also offer several other microarray platforms suitable for copy-number analyses. Here we discuss the application of the CytoScan high-density (HD) platform for the detection of genomic imbalance. We provide an overview of the sequence of computational analyses involved in identifying pathogenic CNVs and highlight important parameters for consideration in assessing the pathogenicity of a detected CNV. © 2015 by John Wiley & Sons, Inc. Copyright © 2015 John Wiley & Sons, Inc.
    Current protocols in human genetics / editorial board, Jonathan L. Haines ... [et al.] 04/2015; 85:8.13.1-8.13.13. DOI:10.1002/0471142905.hg0813s85
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    • "involving the SHANK2 gene, which encodes for a multi-domain molecular scaffolding protein enriched in neuronal synapses. SHANK2 deletions have been associated with autism [39]. Moreover, it has been recently reported that the SHANK2 mutant mouse recapitulates many of the behavioral phenotypes that are typical of ASD [40]. "
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    ABSTRACT: Background The FMR1 premutation is defined as having 55 to 200 CGG repeats in the 5′ untranslated region of the fragile X mental retardation 1 gene (FMR1). The clinical involvement has been well characterized for fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). The behavior/psychiatric and other neurological manifestations remain to be specified as well as the molecular mechanisms that will explain the phenotypic variability observed in individuals with the FMR1 premutation. Methods Here we describe a small pilot study of copy number variants (CNVs) in 56 participants with a premutation ranging from 55 to 192 repeats. The participants were divided into four different clinical groups for the analysis: those with behavioral problems but no autism spectrum disorder (ASD); those with ASD but without neurological problems; those with ASD and neurological problems including seizures; and those with neurological problems without ASD. Results We found 12 rare CNVs (eight duplications and four deletions) in 11 cases (19.6%) that were not found in approximately 8,000 controls. Three of them were at 10q26 and two at Xp22.3, with small areas of overlap. The CNVs were more commonly identified in individuals with neurological involvement and ASD. Conclusions The frequencies were not statistically significant across the groups. There were no significant differences in the psychometric and behavior scores among all groups. Further studies are necessary to determine the frequency of second genetic hits in individuals with the FMR1 premutation; however, these preliminary results suggest that genomic studies can be useful in understanding the molecular etiology of clinical involvement in premutation carriers with ASD and neurological involvement.
    Journal of Neurodevelopmental Disorders 07/2014; 6(1):27. DOI:10.1186/1866-1955-6-27 · 3.27 Impact Factor
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