Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes

Amir, Ruthie; Veyver, Ignatia B. Van den; Schultz, Rebecca; Malicki, Denise; Tran, Charles Q.; Dahle, E. Jill; Philippi, Anne; Timár, L; Percy, Alan K.; Motil, Kathleen J.; Lichtarge, Olivier; Smith, E. O’Brian; Glaze, Daniel G.; Zoghbi, Huda Y.

doi:10.1002/1531-8249(200005)47:5<670::aid-ana20>3.0.co;2-f

Cited by 306 publications

(191 citation statements)

References 38 publications

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“…Consistent with the sporadic occurrence of RTT, most of these mutations occurred de novo at CpG mutation hotspots. 4,5 The majority of the single-nucleotide substitutions are C to T transitions at CpG sites (R106W, R133C, T158M, R306C, R168X, R255X) (71% of all identified MECP2 mutations). 3,6 These sites are hypermutables.…”

Section: Introductionsupporting

confidence: 84%

“…14 Recently, results reported by Amir and colleagues using a more time consuming approach based on the analysis of somatic cell hybrids retaining either the maternal or the paternal X chromosome showed a paternal origin in two cases and a maternal origin in one sporadic case. 5 Moreover, data showing similar results were presented at the American Congress of Human Genetics in Philadelphia. From 26 sporadic cases with a clinical diagnosis of Rett syndrome, 23 have been shown to be from a paternal origin.…”

Section: Discussionmentioning

confidence: 99%

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Parental origin of de novo MECP2 mutations in Rett syndrome

Girard¹,

Couvert²,

Carrié³

et al. 2001

Eur J Hum Genet

109

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Rett syndrome (RTT) is a neurodevelopmental disorder occurring almost exclusively in females as sporadic cases. Recently, DNA mutations in the MECP2 gene have been detected in approximately 70% of patients with RTT. To explain the sex-limited expression of RTT, it has been suggested that de novo X-linked mutations occur exclusively in male germ cells resulting therefore only in affected daughters. To test this hypothesis, we have analysed 19 families with RTT syndrome due to MECP2 molecular defects. In seven informative families we have found by DHPLC a nucleotide variant which could be used to differentiate between the maternal and the paternal allele. In each subject investigated from these families, we have amplified specifically each allele and sequenced allele-specific PCR products to identify the allele bearing the mutation as well as the parental origin of each X chromosome. This approach allowed us to determine the parental origin of de novo mutations in all informative families. In five cases, the de novo MECP2 mutations have a paternal origin and in the two other cases a maternal origin. In all transitions at CpG, the de novo mutation observed was of paternal origin. The high frequency of male germ-line transmission of the mutation (71% of RTT informative cases) is consistent with a predominant occurrence of the disease in females. European Journal of Human Genetics (2001) 9, 231 ± 236.

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Section: Introductionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Parental origin of de novo MECP2 mutations in Rett syndrome

Girard¹,

Couvert²,

Carrié³

et al. 2001

Eur J Hum Genet

109

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“…During normal development, one X chromosome in each cell randomly becomes inactivated, and females display a mosaicism of cells with either paternal or maternal X chromosomes. In the case of RTT, variability in the inactivation of the WT or mutant MeCP2 leads to a spectrum of phenotypic severity (7)(8)(9). Indeed, females with RTT often exhibit nonrandom activation of X chromosomes favoring the WT allele and resulting in subdued phenotypes (9).…”

mentioning

confidence: 47%

Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome

Kim

Hysolli

Park

2011

Proc. Natl. Acad. Sci. U.S.A.

199

183

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Rett syndrome (RTT) is one of the most prevalent female neurodevelopmental disorders that cause severe mental retardation. Mutations in methyl CpG binding protein 2 (MeCP2) are mainly responsible for RTT. Patients with classical RTT exhibit normal development until age 6-18 mo, at which point they become symptomatic and display loss of language and motor skills, purposeful hand movements, and normal head growth. Murine genetic models and postmortem human brains have been used to study the disease and enable the molecular dissection of RTT. In this work, we applied a recently developed reprogramming approach to generate a novel in vitro human RTT model. Induced pluripotent stem cells (iPSCs) were derived from RTT fibroblasts by overexpressing the reprogramming factors OCT4, SOX2, KLF4, and MYC. Intriguingly, whereas some iPSCs maintained X chromosome inactivation, in others the X chromosome was reactivated. Thus, iPSCs were isolated that retained a single active X chromosome expressing either mutant or WT MeCP2, as well as iPSCs with reactivated X chromosomes expressing both mutant and WT MeCP2. When these cells underwent neuronal differentiation, the mutant monoallelic or biallelelic RTT-iPSCs displayed a defect in neuronal maturation consistent with RTT phenotypes. Our in vitro model of RTT is an important tool allowing the further investigation of the pathophysiology of RTT and the development of the curative therapeutics.

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“…Most studies have found an association between skewed X inactivation and a milder phenotype, 17,26,28,31 whereas one study also found an association between skewed X inactivation and a more severe phenotype. 28 Our results support the reported association between a milder phenotype and skewed X inactivation, as we found a higher mean degree of skewing in mild cases than in moderate or severe cases.…”

Section: Discussionmentioning

confidence: 99%

Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers

et al. 2006

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Rett syndrome is a largely sporadic, X-linked neurological disorder with a characteristic phenotype, but which exhibits substantial phenotypic variability. This variability has been partly attributed to an effect of X chromosome inactivation (XCI). There have been conflicting reports regarding incidence of skewed X inactivation in Rett syndrome. In rare familial cases of Rett syndrome, favourably skewed X inactivation has been found in phenotypically normal carrier mothers. We have investigated the X inactivation pattern in DNA from blood and buccal cells of sporadic Rett patients (n ¼ 96) and their mothers (n ¼ 84). The mean degree of skewing in blood was higher in patients (70.7%) than controls (64.9%). Unexpectedly, the mothers of these patients also had a higher mean degree of skewing in blood (70.8%) than controls. In accordance with these findings, the frequency of skewed (XCI Z80%) X inactivation in blood was also higher in both patients (25%) and mothers (30%) than in controls (11%). To test whether the Rett patients with skewed X inactivation were daughters of skewed mothers, 49 mother -daughter pairs were analysed. Of 14 patients with skewed X inactivation, only three had a mother with skewed X inactivation. Among patients, mildly affected cases were shown to be more skewed than more severely affected cases, and there was a trend towards preferential inactivation of the paternally inherited X chromosome in skewed cases. These findings, particularly the greater degree of X inactivation skewing in Rett syndrome patients, are of potential significance in the analysis of genotype -phenotype correlations in Rett syndrome.

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Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes

Cited by 306 publications

References 38 publications

Parental origin of de novo MECP2 mutations in Rett syndrome

Parental origin of de novo MECP2 mutations in Rett syndrome

Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome

Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers

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