A detailed analysis of the MECP2 gene: prevalence of recurrent mutations and gross DNA rearrangements in Rett syndrome patients

Bourdon, Violaine; Philippe, Christophe; Labrune, Orianne; Amsallem, D.; Arnould, Cécile; Jonveaux, Philippe

doi:10.1007/s004390000422

Cited by 76 publications

(65 citation statements)

References 21 publications

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“…Mutations were identified in nine of 13 cases (Table I), yielding a mutation rate of 69%, which is consistent with previous reports [De Bona et al, 2000;Auranen et al, 2001;Bourdon et al, 2001;Laccone et al, 2001;Nicolao et al, 2001;Vacca et al, 2001]. Eight of the nine mutations (89%) were C to T transitions at CpG dinucleotides.…”

Section: Resultssupporting

confidence: 85%

Balanced X chromosome inactivation patterns in the Rett syndrome brain

Shahbazian¹,

Sun²,

Zoghbi³

2002

Am. J. Med. Genet.

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In Rett syndrome (RTT), an X-linked disorder essentially limited to females, neurological development goes awry. Causing this disarray in neuronal function is a mutated form of a protein known as methyl-CpG-binding protein 2 (MeCP2). Because the MECP2 gene is subject to X chromosome inactivation (XCI) in females, a number of studies have addressed whether the percentage of cells inactivating the normal vs. mutant chromosome in heterozygous females influences the phenotypic outcome of MECP2 mutations. Because most of these studies measured XCI in peripheral blood, however, interpretation of the results requires the assumption that XCI patterns in blood are representative of those in the brain, the primarily affected tissue. Here, we have analyzed the MECP2 sequence and XCI status in 13 brains of RTT patients. Mutations were identified in nine of the cases, with eight of these representing C to T transitions at CpG dinucleotides, and one being a novel frameshift mutation (765delA). Patterns of XCI were balanced in 10 of 10 cases for which the assay was informative. As previous studies have shown that a majority of RTT patients have balanced XCI patterns in peripheral blood, our results suggest that the pattern in blood is an accurate indicator of XCI patterns in the brain for a majority of cases, but there are some notable exceptions that this study may help explain. Given the correlation between balanced XCI and classic RTT, these results suggest that a certain percentage of neurons expressing the mutant MECP2 gene may be required for RTT to become manifest.

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Section: Resultssupporting

confidence: 85%

Balanced X chromosome inactivation patterns in the Rett syndrome brain

Shahbazian¹,

Sun²,

Zoghbi³

2002

Am. J. Med. Genet.

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“…This variant in the 3'UTR has been reported previously. 4 In patient 18, a C?G transversion at nucleotide 1141 leads to a novel Proline to Alanine substitution at residue 381 (P381A). Familial analysis in this case indicated that this P381A allele is a benign polymorphism, because the unaffected father carried the same variant.…”

Section: Resultsmentioning

confidence: 99%

MECP2 gene mutation analysis in Chinese patients with Rett syndrome

et al. 2002

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Rett syndrome (RTT) is a progressive neurodevelopmental disorder that affects almost exclusively girls. Mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2) have been found to be a cause. In order to study the spectrum of MECP2 mutations in Chinese patients, we employed PCR and sequencing of the coding region of MECP2 gene in 31 Chinese cases of classical sporadic RTT. Mutations in MECP2 were found in about 55%. Twelve different mutations in exon 3 were identified in 17 of these 31 patients; two of these are novel. A novel missense variant was detected in the C-terminal region in a patient and her father who was normal. In addition, there was a single nucleotide variant in the 3'UTR.

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“…Again, some of the individuals had more than one sequence change, indicating that there is a high variability in the 3 0 UTR. All of the variations encountered were novel, except the c.9964insC [Bourdon et al, 2001]. Ten of the changes were common to both patients and controls, suggesting that they do not have any pathogenic effect.…”

Section: Variation Of the Mecp2 Coding Region And Exon-intron Boundarmentioning

confidence: 89%

MECP2 coding sequence and 3′UTR variation in 172 unrelated autistic patients

Coutinho

Oliveira²,

Katz

et al. 2007

American J of Med Genetics Pt B

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Mutations in the coding sequence of the methyl‐CpG‐binding protein 2 gene (MECP2), which cause Rett syndrome (RTT), have been found in male and female autistic subjects without, however, a causal relation having unequivocally been established. In this study, the MECP2 gene was scanned in a Portuguese autistic population, hypothesizing that the phenotypic spectrum of mutations extends beyond the traditional diagnosis of RTT and X‐linked mental retardation, leading to a non‐lethal phenotype in male autistic patients. The coding region, exon–intron boundaries, and the whole 3′UTR were scanned in 172 patients and 143 controls, by Detection of Virtually All Mutations‐SSCP (DOVAM‐S). Exon 1 was sequenced in 103 patients. We report 15 novel variants, not found in controls: one missense, two intronic, and 12 in the 3′UTR (seven in conserved nucleotides). The novel missense change, c.617G > C (p.G206A), was present in one autistic male with severe mental retardation and absence of language, and segregates in his maternal family. This change is located in a highly conserved residue within a region involved in an alternative transcriptional repression pathway, and likely alters the secondary structure of the MeCP2 protein. It is therefore plausible that it leads to a functional modification of MeCP2. MECP2 mRNA levels measured in four patients with 3′UTR conserved changes were below the control range, suggesting an alteration in the stability of the transcripts. Our results suggest that MECP2 can play a role in autism etiology, although very rarely, supporting the notion that MECP2 mutations underlie several neurodevelopmental disorders. © 2007 Wiley‐Liss, Inc.

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A detailed analysis of the MECP2 gene: prevalence of recurrent mutations and gross DNA rearrangements in Rett syndrome patients

Cited by 76 publications

References 21 publications

Balanced X chromosome inactivation patterns in the Rett syndrome brain

Balanced X chromosome inactivation patterns in the Rett syndrome brain

MECP2 gene mutation analysis in Chinese patients with Rett syndrome

MECP2 coding sequence and 3′UTR variation in 172 unrelated autistic patients

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