In search of a genetic basis for the Rett syndrome

Martinho, Paulo S.; Otto, Priscila Guimarães; Kok, Fernando; Diament, Aron Judka; Marques-Dias, Maria Joaquina; Gonzalez, Claudette Hajaj

doi:10.1007/bf00197693

Cited by 23 publications

(18 citation statements)

References 20 publications

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“…This observation is in agreement with the results of Romeo et al, 14 More et al 15 and Martinho et al 16 Nevertheless, Gilberg et al 17 reported an association between fra(X)(p22) and RS. No such fragility in the short arm of the X-chromosome was found, however, and we consider this fragile site to have no diagnostic significance for RS.…”

Section: Resultssupporting

confidence: 92%

Cytogenetic and molecular-cytogenetic investigation of Rett syndrome

Demidova²,

Ulas³

et al. 1996

NeuroReport

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Section: Resultssupporting

confidence: 92%

Cytogenetic and molecular-cytogenetic investigation of Rett syndrome

Demidova²,

Ulas³

et al. 1996

NeuroReport

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“…Moreover, several studies have shown no increase in parental age, 18,19 or in spontaneous abortions rate among sibs. 20,21 It is not surprising, because such skewed sex ratio might be expected only when the mother is a healthy carrier of the MECP2 mutation (perhaps spared by a skewed, favourable pattern of X inactivation) or bears the mutation in a mosaic state. Moreover, the sex limited expression of Rett syndrome is not complete.…”

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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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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“…C lassic Rett syndrome, affecting 1/10000 to 1/15000 females [Hagberg, 1985;Hagberg and Hagberg, 1997], is a relatively rare disorder, and more than 99% of cases are sporadic new occurrences, which made it initially difficult to hypothesize a genetic inheritance model for this condition [Martinho et al, 1990;Migeon et al, 1995;Zoghbi, 1988]. Various models have been proposed, including uniparental disomy of the X chromosome [Rivkin et al, 1992;Webb et al, 1993], autosomal inheritance with sex-limited expression or triplet repeat expansion mutations [Akesson et al, 1992].…”

mentioning

confidence: 99%

Genetic basis of rett syndrome

Veyver

Zoghbi

2002

Ment. Retard. Dev. Disabil. Res. Rev.

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The origin of Rett syndrome has long been debated, but several observations have suggested an X-linked dominant inheritance pattern. We and others have pursued an exclusion-mapping strategy using DNA from a small number of familial Rett syndrome cases. This work resulted in the narrowing of the region likely to harbor the mutated gene to Xq27.3-Xqter. After systematic exclusion of several candidate genes, we discovered mutations in MECP2, the gene that encodes the transcriptional repressor, methyl-CpG-binding protein 2. Since then, nonsense, missense, or frameshift mutations have been found in at least 80% of girls affected with classic Rett syndrome. Sixty-four percent of mutations are recurrent C > T transitions at eight CpG dinucleotides mutation hotspots, while the C-terminal region of the gene is prone to recurrent multinucleotide deletions (11%). Most mutations are predicted to result in total or partial loss of function of MeCP2. There is no clear correlation between the type and position of the mutation and the phenotypic features of classic and variant Rett syndrome patients, and XCI appears to be a major determinant of phenotypic severity. Further research focuses on the pathogenic consequences of these mutations along the hypothesis of loss of transcriptional repression of a small number of genes that are essential for neuronal function in the maturing brain.

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In search of a genetic basis for the Rett syndrome

Cited by 23 publications

References 20 publications

Cytogenetic and molecular-cytogenetic investigation of Rett syndrome

Cytogenetic and molecular-cytogenetic investigation of Rett syndrome

Parental origin of de novo MECP2 mutations in Rett syndrome

Genetic basis of rett syndrome

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