MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations

Meur, Nathalie Le; Holder‐Espinasse, Muriel; Jaillard, Sylvie; Goldenberg, Alice; Joriot, Sylvie; Amati‐Bonneau, Patrizia; Guichet, Agnès; Barth, Magalie; Charollais, Aude; Journel, Hubert; Auvin, Stéphane; Boucher, Cécile; Kerckaert, Jean‐Pierre; David, Véronique; Manouvrier‐Hanu, Sylvie; Saugier-Veber, Pascale; Frébourg, Thierry; Dubourg, Christèle; Andrieux, Joris; Bonneau, Dominique

doi:10.1136/jmg.2009.069732

Cited by 197 publications

(265 citation statements)

References 30 publications

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“…Rapamycin and mGluR5 modulators are emerging as such potential candidates (Aschrafi et al 2005;Dolen et al 2007;Zhou et al 2009;Gross et al 2010;Osterweil et al 2010;Ehninger and Silva 2011). Transcriptional dysregulation is another potential mechanism occurring in several disorders caused by loss or gain of function of nuclear factors such as MeCP2, CREB-binding protein (Petrij et al 1995), EP300 (Roelfsema et al 2005), or MEF2C (Le Meur et al 2010) (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities

Zoghbi

Bear

2012

Cold Spring Harbor Perspectives in Biology

665

589

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The discovery of the genetic causes of syndromic autism spectrum disorders and intellectual disabilities has greatly informed our understanding of the molecular pathways critical for normal synaptic function. The top-down approaches using human phenotypes and genetics helped identify causative genes and uncovered the broad spectrum of neuropsychiatric features that can result from various mutations in the same gene. Importantly, the human studies unveiled the exquisite sensitivity of cognitive function to precise levels of many diverse proteins. Bottom-up approaches applying molecular, biochemical, and neurophysiological studies to genetic models of these disorders revealed unsuspected pathogenic mechanisms and identified potential therapeutic targets. Moreover, studies in model organisms showed that symptoms of these devastating disorders can be reversed, which brings hope that affected individuals might benefit from interventions even after symptoms set in. Scientists predict that insights gained from studying these rare syndromic disorders will have an impact on the more common nonsyndromic autism and mild cognitive deficits.

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Section: Discussionmentioning

confidence: 99%

Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities

Zoghbi

Bear

2012

Cold Spring Harbor Perspectives in Biology

665

589

View full text Add to dashboard Cite

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“…Histone deacetylases (HDACs) are involved in neuronal dendritic growth regulation and regulate transcription factors activity associated to ASD or intellectual disability, such as MECP2 49 or MEF2C. 50,51 One may speculate that the alternative transcribed protein, missing the nuclear export signal, may have a dominant negative effect. However, we failed to demonstrate any altered splicing in mRNA extracted from the patient lymphoblastoid cells.…”

Section: Splicing Alterations Of Gaba R Genes In Autismmentioning

confidence: 99%

Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals

et al. 2012

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A large-scale sequencing screen of X-linked synaptic genes in individuals with autism spectrum disorder (ASD) or schizophrenia (SCZ), two common neurodevelopmental disorders, identified many variants most of which have no easily predictable effect on gene function. In this report, we evaluated the impact of these rare missense and silent variants on gene splicing. For this purpose, we used complementary in silico analyses, in vitro minigene-based assays and RNA prepared from lymphoblastoid cells derived from patients with these mutations. Our goal was to identify the variants which might either create or disrupt an acceptor splice site, a donor splice site or an exonic splicing enhancer, thus leading to aberrant splicing that could be involved in the pathogenesis of ASD or SCZ. We identified truncating mutations in distinct X-linked gamma-aminobutyric acid A (GABA A) receptor subunit-encoding genes, GABRQ and GABRA3, in two different families. Furthermore, missense and silent variants in nuclear RNA export factor 5 and histone deacetylase 6 were shown to partially disrupt the protein. While genes from the GABAergic pathway have previously been thought to be involved in the pathophysiology of ASD, this is the first report of ASD patients with truncating mutations in GABA receptors genes.

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“…For example, several groups have now reported on unrelated pediatric cases of 5q14.3-q15 genomic losses detected using aCGH or single nucleotide polymorphism arrays. [15][16][17] Patients were identified in infancy or early childhood, with the oldest reported patient being 7 years old. The common overlapping phenotypes include severe intellectual disability, central nervous system abnormalities, hypotonia, and seizures.…”

Section: Discussionmentioning

confidence: 99%

High prevalence of array comparative genomic hybridization abnormalities in adults with unexplained intellectual disability

Taylor

Jirikowic

Wells

et al. 2010

Genetics in Medicine

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Purpose: Array comparative genomic hybridization is now a widely used clinical tool for the evaluation of intellectual disability. The current 10% yield of positive findings is based largely on pediatric data. Adults with unexplained intellectual disability have not been systematically studied with array comparative genomic hybridization. Here, we report our initial experience with array comparative genomic hybridization testing on 45 adults with unexplained intellectual disability referred to an adult genetics clinic. Methods: Beginning in 2006, we applied clinically available array comparative genomic hybridization testing to adults referred with an intellectual disability phenotype. The initial platform used was an early generation targeted or constitutional array, which was replaced by our current platform using more than 5000 bacterial artificial chromosome clones with an average resolution of 500 Kb and targeting 114 disease loci. All patients also underwent highresolution karyotype analysis and molecular testing for Fragile X syndrome. Results: Our population comprised 45 patients with unexplained intellectual disability (18 men and 27 women) with an average age of 35.1 years. Most patients had not been evaluated by genetics clinics since childhood or had never undergone a genetic evaluation; only two had documentation of prior normal karyotype studies. Three subjects had abnormal high-resolution chromosome studies, which were also confirmed by array comparative genomic hybridization. Seven of the remaining 42 patients (17%) had novel genomic losses identified only by array comparative genomic hybridization. Conclusion: Abnormal genomic losses detected by array comparative genomic hybridization are prevalent in adults with unexplained intellectual disability. Our data showing abnormalities in 22% and 17% of overall patients and of cases with normal karyotypes, respectively, suggest that the yield of array comparative genomic hybridization in adults with unexplained intellectual disability may be higher than in pediatric populations. Genet Med 2010:12(1):32-38.

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MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations

Abstract: Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations.

Cited by 197 publications

References 30 publications

Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities

Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities

Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals

High prevalence of array comparative genomic hybridization abnormalities in adults with unexplained intellectual disability

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