Characterization of the full fragile X syndrome mutation in fetal gametes

  title={Characterization of the full fragile X syndrome mutation in fetal gametes},
  author={Henry E. Malter and Jane Iber and Ralph A. Willemsen and Esther de Graaff and Jack C Tarleton and Jaakko Leisti and Stephen T. Warren and Ben A. Oostra},
  journal={Nature Genetics},
Fragile X syndrome results from the expansion of the CGG repeat in the FMR1 gene. Expansion has been suggested to be a postzygotic event with the germline protected. From an analysis of intact ovaries of full mutation fetuses, we now show that only full expansion alleles can be detected in oocytes (but in the unmethylated state). Similarly, the testes of a 13-week full mutation fetus show no evidence of premutations while a 17-week full mutation fetus exhibits some germ cells with attributes of… 

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.

Demethylation, reactivation, and destabilization of human fragile X full-mutation alleles in mouse embryocarcinoma cells.

The results strongly support the idea that fully expanded alleles are initially unstable and unmethylated in the human embryo and gain stability upon genetic or epigenetic change of the embryonic cells.

Fragile X full mutation alleles composed of few alleles: Implications for CGG repeat expansion

The hypothesis that the FMR1 CGG repeat instability is limited to very early embryogenesis in the soma is supported and the omission of ethidium bromide will facilitate the diagnosis of females with full mutation alleles is facilitated.

A unique case of reversion to normal size of a maternal premutation FMR1 allele in a normal boy

This is the first non-mosaic case of reduction in the CGG tract of the FMR1 gene, resulting in a normal allele, and Haplotype analysis proved that the rearranged allele originated from the maternal expanded allele.

Nonrandom X inactivation and selection of fragile X full mutation in fetal fibroblasts.

Cl cloning and serial cultivation indicate the possibility of selection depending on the activation status of the expanded X chromosome in fetal FM female fibroblasts.

Preimplantation diagnosis for fragile X syndrome based on the detection of the non‐expanded paternal and maternal CGG

It is reported here for the first time a method for preimplantation genetic diagnosis (PGD) for fragile X syndrome based on the amplification of the CGG triplet in the normal allele.

Unexpected finding of a paternal premutation of the fragile X FMR1 gene in a female fetus of a premutation carrier mother

Although a parental couple composed of two premutation carriers is rare, this case illustrates the importance of characterizing both parental genotypes when the results of prenatal diagnosis suggest an unusual segregation of the mutant and/or normal allele.

X Frágil

The diagnosis of FXS has evolved from karyotype with special culture medium, to molecular techniques that are more sensitive and specific including PCR and Southern Blot, which has led to the development of investigations on pharmaceutical management or targeted treatments for FXS.

Animal model for fragile X syndrome.

Functional studies on the FMR1 protein have shown that the protein can bind RNA and might be involved in transport of RNAs from the nucleus to the cytoplasm and a role of F MR1 protein on translation of certain mRNAs has been suggested.



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

Study of FMR–1 in sperm of four male fragile X patients showed that only the premutation was present in their sperm, although they had a full mutation in peripheral lymphocytes, which might suggest that expansion of the premutations to the full mutations in FMR-1 does not occur in meiosis but in a postzygotic stage.

Analysis of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development.

The results validate the analysis of chorionic villi for direct prenatal diagnosis of the fragile X syndrome and indicate that somatic heterogeneity of the full mutation is established during the very early stages of embryogenesis.

Population dynamics of a meiotic/mitotic expansion model for the fragile X syndrome.

A model to explain the mutational process and population dynamics of the fragile X syndrome is presented and a specific premutation-allele frequency distribution is predicted and differs from that based on models assuming only meiotic expansion.

Mitotic stability of fragile X mutations in differentiated cells indicates early post–conceptional trinucleotide repeat expansion

We demonstrate hre that somatic variation of CGG repeat length is based on a mosaic of cells with different but stable FMR–1 alleles and does not reflect permanent mitotic instability. The length of

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.

Advances in molecular analysis of fragile X syndrome.

Advances have led to highly accurate laboratory diagnoses of both carrier and affected individuals as well as markedly improved prenatal diagnosis, and a previously unrecognized class of mutation, later found responsible for several other important genetic diseases, has emerged.

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.

On the parental origin of de novo mutation in man.

Temporal disturbance of meiotic progression seems likely to underly aneuploidy production in the female mouse, and this could equally be true in women, most especially as they approach the menopause when irregular cyclicity sets in.