MECP2 Mutations in Sporadic Cases of Rett Syndrome Are Almost Exclusively of Paternal Origin

Trappe, Ralf Ulrich; Laccone, Franco; Cobilanschi, Joana; Meins, Moritz; Huppke, Peter; Hanefeld, F.; Engel, Wolfgang

doi:10.1086/320109

Cited by 239 publications

(184 citation statements)

References 28 publications

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“…None of the sequence variants found in the control samples have been reported as pathogenic mutations in previous studies. Of the sequence changes observed in this study, three were common to both patients and controls (c.378-19delT, p.A131A, and p.T445T), suggesting that they are polymorphisms with no pathogenic effect, as reported before [Trappe et al, 2001;Kleefstra et al, 2004].…”

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

confidence: 66%

“…Of these, four are missense changes observed in males, of which one is novel. In addition, we found four silent and three intronic changes (two novel); of these, two silent and one intronic change were also present in the controls, and have been previously reported [Trappe et al, 2001;Kleefstra et al, 2004]. The novel missense change is a c.617G > C transition found in one autistic male, resulting in a p.G206A amino acid replacement in the inter-domain region of MeCP2, and was not found in 143 controls.…”

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

confidence: 61%

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

confidence: 66%

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

confidence: 61%

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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“…Previous reports indicated that the paternal type of inheritance constitutes more than 90% sporadic RTT cases (Trappe et al, 2001; Zhang, Bao, Cao, et al, 2012; Zhang, Bao, Zhang, et al, 2012). However, in our familial cases, all mutated MECP2 were inherited from their mothers.…”

Section: Discussionmentioning

confidence: 98%

Familial cases and male cases with MECP2 mutations

Zhang

Zhao

Bao

et al. 2017

American J of Med Genetics Pt B

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This is the first report of Chinese familial cases with Rett syndrome (RTT) or X‐linked mental retardation (XLMR). RTT is a neurodevelopmental disorder that almost exclusively affects females. Most RTT cases are sporadic. We have studied eight cases with MECP2 mutations in six Chinese families, including three females and five males with RTT or XLMR. All shared identical MECP2 mutations with their mothers. The three females fulfilled the diagnostic criteria for RTT, while the five males were XLMR. A random X‐chromosome inactive (XCI) pattern was seen in all the three female patients and two mothers while a skewed XCI in the rest four mothers. The clinical manifestations and pathogenic gene spectrum between male and female patients were different. The different MECP2 mutations and different XCI pattern may be the determinants of the phenotypic heterogeneity between the family members.

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“…As such, the majority of de novo mutations occur in the sperm [46,47]. In some instances, the mutation is transmitted by a female carrying a specific mutation but, owing to favorable XCI, she is unaffected or has mild learning disability or cognitive impairment [48,49].…”

Section: Geneticsmentioning

confidence: 99%

Rett Syndrome: Reaching for Clinical Trials

2015

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Rett syndrome (RTT) is a syndromic autism spectrum disorder caused by loss-of-function mutations in MECP2. The methyl CpG binding protein 2 binds methylcytosine and 5-hydroxymethycytosine at CpG sites in promoter regions of target genes, controlling their transcription by recruiting co-repressors and co-activators. Several preclinical studies in mouse models have identified rational molecular targets for drug therapies aimed at correcting the underlying neural dysfunction. These targeted therapies are increasingly translating into human clinical trials. In this review, we present an overview of RTT and describe the current state of preclinical studies in methyl CpG binding protein 2-based mouse models, as well as current clinical trials in individuals with RTT.

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MECP2 Mutations in Sporadic Cases of Rett Syndrome Are Almost Exclusively of Paternal Origin

Cited by 239 publications

References 28 publications

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

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

Familial cases and male cases with MECP2 mutations

Rett Syndrome: Reaching for Clinical Trials

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