Analysis of the Parental Origin of De Novo <i>MECP2</i> Mutations and X Chromosome Inactivation in 24 Sporadic Patients With Rett Syndrome in China

Zhu, Xing-wang; Li, Meirong; Pan, Hong; Bao, Xinhua; Zhang, Jingjing; Wu, Xiru

doi:10.1177/0883073809350722

Cited by 17 publications

(19 citation statements)

References 29 publications

(54 reference statements)

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“…Furthermore, the male germline accumulates more DNA replication errors because of the higher number of germline cell divisions in males than females [28]. Therefore, PHEX mutagenesis in paternal germ cells is likely more frequent in sporadic patients and would only affect the female offspring [24], [29], which is accordance with our finding from family 9 (proband III1 is female). Interestingly, however, that the 2 sporadic patients (probands from family 7 and 8) in our study are males, which differs from the demographics in previous studies.…”

Section: Discussionsupporting

confidence: 90%

Identification of Two Novel Mutations in the PHEX Gene in Chinese Patients with Hypophosphatemic Rickets/Osteomalacia

Yue

et al. 2014

PLoS ONE

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ObjectiveX-linked dominant hypophosphatemia (XLH) is the most prevalent form of inherited rickets/osteomalacia in humans. The aim of this study was to identify PHEX gene mutations and describe the clinical features observed in 6 unrelated Chinese families and 3 sporadic patients with hypophosphatemic rickets/osteomalacia.MethodsFor this study, 45 individuals from 9 unrelated families of Chinese Han ethnicity (including 16 patients and 29 normal phenotype subjects), and 250 healthy donors were recruited. All 22 exons and exon-intron boundaries of the PHEX gene were amplified by polymerase chain reaction (PCR) and directly sequenced.ResultsThe PHEX mutations were detected in 6 familial and 3 sporadic hypophosphatemic rickets/osteomalacia. Altogether, 2 novel mutations were detected: 1 missense mutation c.1183G>C in exon 11, resulting in p.Gly395Arg and 1 missense mutation c.1751A>C in exon 17, resulting in p.His584Pro. No mutations were found in the 250 healthy controls.ConclusionsOur study increases knowledge of the PHEX gene mutation types and clinical phenotypes found in Chinese patients with XLH, which is important for understanding the genetic basis of XLH. The molecular diagnosis of a PHEX genetic mutation is of great importance for confirming the clinical diagnosis of XLH, conducting genetic counseling, and facilitating prenatal intervention, especially in the case of sporadic patients.

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Section: Discussionsupporting

confidence: 90%

Identification of Two Novel Mutations in the PHEX Gene in Chinese Patients with Hypophosphatemic Rickets/Osteomalacia

Yue

et al. 2014

PLoS ONE

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“…Indeed, phenotypic variations seen in Rett Syndrome are presumably dependent on the X-inactivation status of the patient [92, 93]. However, recent studies also implicate other factors [94, 95]. The MECP2 locus on the X-chromosome is drawn inside the Xist silencing compartment at day 4 after differentiation [63].…”

Section: Therapeutic Applications Of Manipulating Lncrna Mediated Silmentioning

confidence: 99%

Long non‐coding RNA modifies chromatin

2011

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Common themes are emerging in the molecular mechanisms of long non-coding RNA-mediated gene repression. Long non-coding RNAs (lncRNAs) participate in targeted gene silencing through chromatin remodelling, nuclear reorganisation, formation of a silencing domain and precise control over the entry of genes into silent compartments. The similarities suggest that these are fundamental processes of transcription regulation governed by lncRNAs. These findings have paved the way for analogous investigations on other lncRNAs and chromatin remodelling enzymes. Here we discuss these common mechanisms and provide our view on other molecules that warrant similar investigations. We also present our concepts on the possible mechanisms that may facilitate the exit of genes from the silencing domains and their potential therapeutic applications. Finally, we point to future areas of research and put forward our recommendations for improvements in resources and applications of existing technologies towards targeted outcomes in this active area of research.

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“…Whether single base pair deletions are more frequently maternally derived is yet to be investigated. In two previously reported cases with sporadic RTT, the frameshift mutations (c.806delG and c.677insA) occurred on the maternally derived X chromosome [5,7]. Together these results indicate that frameshift mutations involving only a single base pair have a tendency to be of maternal origin than first anticipated, but as listed in Table 3 the familial mutations are not predominated by single base pair deletions or insertions.…”

Section: Discussionmentioning

confidence: 57%

“…As summarized in table 3 more than half of the families with RTT have a frameshift mutation, and a clear correlation exists between the XCI profile in blood and the phenotypes of the respective family members. It is known from cases with sporadic RTT, that over 70% have the C > T transition, (RettBASE, http://mecp2.chw.edu.au), which are almost exclusively of paternal origin [4-7] and the blood XCI profiles do not correlate with their phenotypes [29]. Therefore another segregation mechanism may exist for MECP2 frameshift mutations, which can influence a more favourable phenotype, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Small C-terminal deletions, with one or both breakpoints located within the "deleted prone region" (DPR) of exon 4, account for 10% of the cases [3]. The vast majority of RTT cases are sporadic (> 99%) and four studies have shown that the eight common C > T transition mutations arise almost exclusively on the paternally derived X chromosome in sporadic cases [4-7]. So far, the parental origin of de novo frameshift mutations has not been investigated in large cohorts of RTT cases.…”

Section: Introductionmentioning

confidence: 99%

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Two new Rett syndrome families and review of the literature: expanding the knowledge of MECP2 frameshift mutations

Ravn

Roende

Dunø

et al. 2011

Orphanet Journal of Rare Diseases

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BackgroundRett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder, which is usually caused by de novo mutations in the MECP2 gene. More than 70% of the disease causing MECP2 mutations are eight recurrent C to T transitions, which almost exclusively arise on the paternally derived X chromosome. About 10% of the RTT cases have a C-terminal frameshift deletion in MECP2. Only few RTT families with a segregating MECP2 mutation, which affects female carriers with a phenotype of mental retardation or RTT, have been reported in the literature. In this study we describe two new RTT families with three and four individuals, respectively, and review the literature comparing the type of mutations and phenotypes observed in RTT families with those observed in sporadic cases. Based on these observations we also investigated origin of mutation segregation to further improve genetic counselling.MethodsMECP2 mutations were identified by direct sequencing. XCI studies were performed using the X-linked androgen receptor (AR) locus. The parental origin of de novo MECP2 frameshift mutations was investigated using intronic SNPs.ResultsIn both families a C-terminal frameshift mutation segregates. Clinical features of the mutation carriers vary from classical RTT to mild mental retardation. XCI profiles of the female carriers correlate to their respective geno-/phenotypes. The majority of the de novo frameshift mutations occur on the paternally derived X chromosome (7/9 cases), without a paternal age effect.ConclusionsThe present study suggests a correlation between the intrafamilial phenotypic differences observed in RTT families and their respective XCI pattern in blood, in contrast to sporadic RTT cases where a similar correlation has not been demonstrated. Furthermore, we found de novo MECP2 frameshift mutations frequently to be of paternal origin, although not with the same high paternal occurrence as in sporadic cases with C to T transitions. This suggests further investigations of more families. This study emphasizes the need for thorough genetic counselling of families with a newly diagnosed RTT patient.

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Analysis of the Parental Origin of De Novo MECP2 Mutations and X Chromosome Inactivation in 24 Sporadic Patients With Rett Syndrome in China

Cited by 17 publications

References 29 publications

Identification of Two Novel Mutations in the PHEX Gene in Chinese Patients with Hypophosphatemic Rickets/Osteomalacia

Identification of Two Novel Mutations in the PHEX Gene in Chinese Patients with Hypophosphatemic Rickets/Osteomalacia

Long non‐coding RNA modifies chromatin

Two new Rett syndrome families and review of the literature: expanding the knowledge of MECP2 frameshift mutations

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