The full mutation in the FMR–1 gene of male fragile X patients is absent in their sperm

  title={The full mutation in the FMR–1 gene of male fragile X patients is absent in their sperm},
  author={Edwin Reyniers and Lieve Vits and Kristel De Boulle and Bernadette Van Roy and D{\'e}sir{\'e}e Van Velzen and Esther de Graaff and Annemieke J M H Verkerk and H Z Jorens and John K. Darby and Ben A. Oostra and Patrick J. Willems},
  journal={Nature Genetics},
Fragile X syndrome is characterized at the molecular level by amplification of a (CGG)n repeat and hypermethylation of a CpG island preceeding the open reading frame of the fragile X gene (FMR–1) located in Xq27.3. Anticipation in this syndrome is associated with progressive amplification of the (CGG)n repeat from a premutation to a full mutation through consecutive generations. Remarkably, expansion of the premutation to the full mutation is strictly maternal. To clarify this parental… 

Instability of the CGG repeat and expression of the FMR1 protein in a male fragile X patient with a lung tumor.

The results found in the tumor suggest that the CpGs in these restriction sites are not essential for regulation of FMR1 expression, and there is a need for a more accurate study of the exact promoter of F MRP.

Unexpected Inheritance of the (CGG)n Trinucleotide Expansion in a Fragile X Syndrome Family

Findings from this family study corroborate the hypothesis that the expansion during female transmission could be a postzygotic event and raise the problem of mosaicism.

The fragile X mutation

Possible mechanisms of expansion in light of the unusual structural properties proposed for CGG repeats are discussed and various other folate-sensitive fragile sites that are also caused by unstable expansions of CGG (CCG) repeats are being cloned and characterized.

Transition from premutation to full mutation in fragile X syndrome is likely to be prezygotic.

Analysis of tissues from affected fetuses indicate that such a putative postzygotic transition would have to occur very early in embryogenesis and most likely before determination of germ cell lineage, and it is proposed that this is strong, albeit indirect evidence against a postzyGotic transition to FM.

Postmortem examination of two fragile X brothers with an FMR1 full mutation.

No evidence for extensive mitotic expansion of the CGG repeat during fetal or postnatal life of a fragile X patient was found, in contrast to dynamic mutations caused by CAG/CTG repeat expansion.

Fragile X syndrome and the (CGG)n mutation: two families with discordant MZ twins.

Two families in which discordance between two sets of MZ twins illustrates two important genetic points are presented, demonstrating in vivo mitotic instability of this CGG repeat and suggesting that the transition to the full mutation occurred postzygotically.

Characterization of the full fragile X syndrome mutation in fetal gametes

Analysis of intact ovaries of full mutation fetuses shows that only full expansion alleles can be detected in oocytes (but in the unmethylated state), discounting the hypothesis that the germline is protected from full expansion and suggest full mutation contraction in the immature testis.

Reversion to Normal of FMR1 Expanded Alleles: A Rare Event in Two Independent Fragile X Syndrome Families

Two unaffected boys in two independent FXS families who inherited a non-mosaic allele in the normal and intermediate range, respectively, from their mothers who are carriers of an expanded CGG allele are described.

Paternal transmission of fragile X syndrome

A family in which a fragile X mosaic male has a daughter with both premutation and partially methylated full mutation alleles and a significant developmental disability is presented, the first report of such an occurrence and it challenges current thinking about the expansion and transmission of unstable FMR1 alleles from men to their daughters.



A point mutation in the FMR-1 gene associated with fragile X mental retardation

The results suggest that mutations in FMR–1 are directly responsible for fragile X syndrome, irrespective of possible secondary effects caused by FRAXA.

Mental Status and Fragile X Expression in Relation to FMR-1 Gene Mutation

A less frequent occurrence of additional premutation alleles in adult patients compared with juveniles, suggesting a continued mitotic instability in life and the presence of a full mutation in the FMR-1 gene seemed decisive for the occurrence of mental impairment in the patient.

DNA methylation represses FMR-1 transcription in fragile X syndrome.

Preliminary prenatal diagnosis of a male fetus with fragile X syndrome is reported by utilizing molecular differences and indicates that the abnormal methylation of the FMR-1 CpG-island is responsible for the absence of F MRM-1 transcription and suggests that the methylation may be acquired early in embryogenesis.

A microdeletion of less than 250 kb, including the proximal part of the FMR-I gene and the fragile-X site, in a male with the clinical phenotype of fragile-X syndrome.

Evidence is presented that a deletion including the HTF island and exons of the FMR-1 gene was detected in a fragile X-negative mentally retarded male who presented the clinical phenotype of the fragile-X syndrome.

Segregation of the fragile X mutation from an affected male to his normal daughter.

We report here a family in which the fragile X mutation segregates from an affected grandfather through his normal daughter to an affected grandson. The grandson shows clinical and cytogenetic

Fragile X syndrome without CCG amplification has an FMR1 deletion

The patient has a previously uncharacterized submicroscopic deletion encompassing the CCG repeat, the entire FMR1 gene and about 2.5 megabases of flanking sequences, confirming that the fragile X phenotype can exist, without amplification of theCCG repeat or cytogenetic expression of the fragileX.

Inheritance of the fragile X syndrome: size of the fragile X premutation is a major determinant of the transition to full mutation.

The fragile X mental retardation syndrome is caused by unstable expansion of a CGG repeat and direct detection of the mutations is used to characterise large families who illustrate the wide variation in penetrance which has been observed in different sibships (a feature often called the Sherman paradox).

Abnormal pattern detected in fragile-X patients by pulsed-field gel electrophoresis

To detect rearrangements, or methylation changes that may reflect a locally inactive X chromosome, pulsed-field gel analysis of DNA from fragile-X patients with probes close to the fragile- X locus was used.