Three Rett patients with both MECP2 mutation and 15q11–13 rearrangements

Longo, Ilaria; Russo, Luisa; Meloni, Ilaria; Ricci, Iolanda; Ariani, Francesca; Pescucci, Chiara; Giordano, Carmela Tiziana; Canitano, Roberto; Hayek, Joussef; Zappella, Michele; Neri, Giovanni; Renieri, Alessandra; Gurrieri, Fiorella

doi:10.1038/sj.ejhg.5201198

Cited by 13 publications

(8 citation statements)

References 23 publications

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“…Although rare, MECP2 mutations have been reported in individuals clinically diagnosed with AS or autism (56,57), and MECP2 mutations combined with rearrangements in 15q11-13 have been reported in individuals with RTT (58). In this study we show that GABRB3, a 15q11-13 gene, is positively regulated by MeCP2 and significantly reduced in both RTT and AS.…”

Section: Discussionsupporting

confidence: 52%

15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders

Hogart

Nagarajan

Patzel

et al. 2007

Human Molecular Genetics

219

173

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Human chromosome 15q11-13 is a complex locus containing imprinted genes as well as a cluster of three GABA A receptor subunit (GABR) genes, GABRB3, GABRA5, and GABRG3. Deletion or duplication of 15q11-13 GABR genes occurs in multiple human neurodevelopmental disorders including Prader-Willi syndrome (PWS), Angelman syndrome (AS), and autism. GABRB3 protein expression is also reduced in Rett syndrome (RTT), caused by mutations in MECP2 on Xq28. Although Gabrb3 is biallelically expressed in mouse brain, conflicting data exist regarding the imprinting status of the 15q11-13 GABR genes in humans. Using coding single nucleotide polymorphisms we show that all three GABR genes are biallelically expressed in 21 control brain samples, demonstrating that these genes are not imprinted in normal human cortex. Interestingly, four of eight autism and one of five RTT brain samples showed monoallelic or highly skewed allelic expression of one or more GABR gene, suggesting that epigenetic dysregulation of these genes is common to both disorders. Quantitative real-time RT-PCR analysis of PWS and AS samples with paternal and maternal 15q11-13 deletions revealed a paternal expression bias of GABRB3, while RTT brain samples showed a significant reduction in GABRB3 and UBE3A. Chromatin immunoprecipitation and bisulfite sequencing in SH-SY5Y neuroblastoma cells demonstrated that MeCP2 binds to methylated CpG sites within GABRB3. Our previous studies demonstrated that homologous 15q11-13 pairing in neurons was dependent on MeCP2 and was disrupted in RTT and autism cortex. Combined these results suggest that MeCP2 acts as a chromatin organizer for optimal expression of both alleles of GABRB3 in neurons.

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Section: Discussionsupporting

confidence: 52%

15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders

Hogart

Nagarajan

Patzel

et al. 2007

Human Molecular Genetics

219

173

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“…Additional genetic alterations have been associated with the RTT phenotype, even in patients with a typical MeCP2 mutation. Longo et al 21 recently reported three patients with Rett syndrome and rearrangements of chromosome 15q11-13, a region known to be implicated in autistic phenotypes. 21 This suggests the possibility of the role of additional genes with the RTT phenotype, although further studies are necessary to confirm this association.…”

Section: Discussionmentioning

confidence: 99%

“…Longo et al 21 recently reported three patients with Rett syndrome and rearrangements of chromosome 15q11-13, a region known to be implicated in autistic phenotypes. 21 This suggests the possibility of the role of additional genes with the RTT phenotype, although further studies are necessary to confirm this association. Indeed, in a recent review of Weaving et al 22 , at least seven published atypical RTT cases have been found to have mutation in the Xlinked CDKL5/STK9 gene.…”

Section: Discussionmentioning

confidence: 99%

Clinical Stringency Greatly Improves Mutation Detection in Rett Syndrome

Gauthier

Amorim

Mnatzakanian

et al. 2005

Can. j. neurol. sci.

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Rett Syndrome (RTT, OMIM 312750) is characterized by onset in the first 18 months of life of slowing and arrest of neurodevelopment paralleled with a loss of communication and motor skills acquired to that point. Purposeful hand movements are replaced by a semi-continuous hand-washing stereotype. Social interaction with the family disintegrates, resembling autistic withdrawal and, with the passage of time, a picture of profound mental retardation emerges. 1 However, depending on mutation location and extent of X-inactivation skewing, individuals with RTT may also exhibit milder phenotypes with preserved speech and ambulation, mild learning disability, or a clinical picture more similar to autism than to classical RTT. [2][3][4] Because of X-linkage, mutations causing classical RTT in girls are generally embryonic-lethal in boys, although some rare mild mutations allow survival and a variety of neurodevelopmental phenotypes in males. [5][6][7] Following mapping of the RTT candidate locus to Xq27-28, the use of a candidate gene approach allowed identification of ABSTRACT: Background: Rett syndrome (RTT) is a severe neurodevelopmental disorder of girls, caused by mutations in the X-linked MECP2 gene. Worldwide recognition of the RTT clinical phenotype in the early 1980's allowed many cases to be diagnosed, and established RTT as one of the most common mental retardation syndromes in females. The years since then led to a refinement of the phenotype and the recent elaboration of Revised Diagnostic Criteria (RDC). Here, we study the impact of the presence versus the absence of the use of diagnostic criteria from the RDC to make a diagnosis of RTT on MECP2 mutation detection in Canadian patients diagnosed and suspected of having RTT. Methods: Using dHPLC followed by sequencing in all exons of the MECP2 gene, we compared mutation detection in a historic cohort of 35 patients diagnosed with RTT without the use of specific diagnostic criteria to a separate more recent group of 101 patients included on the basis of strict fulfillment of the RDC. Results: The MECP2 mutation detection rate was much higher in subjects diagnosed using a strict adherence to the RDC (20% vs. 72%). Conclusions: These results suggest that clinical diagnostic procedures significantly influence the rate of mutation detection in RTT, and more generally emphasize the importance of diagnostic tools in the assessment of neurobehavioral syndromes.RÉSUMÉ: Un examen clinique rigoureux améliore beaucoup la détection de mutations dans le syndrome de Rett. Introduction: Le syndrome de Rett (RTT) est une maladie neurodéveloppementale sévère observée chez les filles et causée par des mutations du gène MECP2 situé sur le chromosome X. L'identification à l'échelle mondiale du phénotype clinique du RTT au début des années 1980 a permis de diagnostiquer de nombreux cas et a démontré que le RTT est un des syndromes de retard mental les plus fréquents chez les filles. Depuis, la description du phénotype a été raffinée et des critères diagnostiques révisés (CDR) ont ...

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“…Methylation Specific PCR (MSPCR) analysis of SNRPN on DNA treated with sodium bisulfate (EZ DNA Methylation-Gold™) was performed (Kitsiou-Tzeli et al, 2010). In order to determine the parental origin of the 15q11.2 deletion (case 4), microsatellite markers D15S6A and nt5898 (Longo et al, 2004;Buiting et al, 2007) were studied on DNA from the patient and her parents by PCR and fragment analysis.…”

Section: Dna Methylation Analysis and Microsatellite Analysis For Thementioning

confidence: 99%

Microdeletion and microduplication 17q21.31 plus an additional CNV, in patients with intellectual disability, identified by array-CGH

Kitsiou-Tzeli

Frysira

Γιαννίκου

et al. 2012

Gene

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Three Rett patients with both MECP2 mutation and 15q11–13 rearrangements

Cited by 13 publications

References 23 publications

15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders

15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders

Clinical Stringency Greatly Improves Mutation Detection in Rett Syndrome

Microdeletion and microduplication 17q21.31 plus an additional CNV, in patients with intellectual disability, identified by array-CGH

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