Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox

  title={Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox},
  author={Ying-Hui Fu and Derek P.A. Kuhl and Antonio Pizzuti and Maura Pieretti and James S. Sutcliffe and Stephen Richards and Annemieke J.M.H. Verkert and Jeanette J. A. Holden and Raymond G. Fenwick and Stephen T. Warren and Ben A. Oostra and David L Nelson and Charles Thomas Caskey},

Data on the CGG repeat at the fragile X site in the non-retarded Japanese population and family suggest the presence of a subgroup of normal alleles predisposing to mutate

Observations in the Japanese population suggest that a subgroup is present in normal alleles of FMR-1 and that this sub group is more liable to mutate than others.

Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles.

The smallest premutation alleles that expanded to a full mutation (>200 repeats) in one generation contained 59 repeats; sequence analysis of the 59-repeat alleles from these two females revealed no AGG interruptions within the FMR1 CGG repeat.

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.

Microdeletion in the FMR-1 gene: an apparent null allele using routine clinical PCR amplification

A patient referred for fragile X testing who was found to carry an apparent null allele by PCR amplification of the CGG repeat region of the FMR-1 gene is reported here.

Decrease in the CGGn trinucleotide repeat mutation of the fragile X syndrome to normal size range during paternal transmission.

The results suggest an intergenerational reduction in the CGGn repeat from premutation size to the normal size range and stable transmission of the contracted repeat to the next generation.

Population genetics of the FRAXE and FRAXF GCC repeats, and a novel CGG repeat, in Xq28.

An analysis of repeats at two fragile site loci, FRAXE and FRAxF, and a novel CGG repeat in Xq28, in five different human populations, which suggests that these loci may also be subject to the same mutation process.

Stability of triplet repeats of myotonic dystrophy and fragile X loci in human mutator mismatch repair cell lines

Analysis of the triplet repeat regions of the DM and fragile X mental retardation loci in cell lines HTC116 and LoVo indicated that the size of the endogenous (CTG)n and (CGG)n tracts fall within the range observed in the normal population.

Mosaicism for the full mutation and a microdeletion involving the CGG repeat and flanking sequences in the FMR1 gene in eight fragile X patients.

Sequencing analysis of the deletion breakpoints in 6 patients demonstrated an internal deletion confined to the CGG repeat in four of them, which represents the most likely explanation for the regression of the full mutation to a normal sized allele.

Apparent regression of the CGG repeat in FMR1 to an allele of normal size

A family is presented in which the number of repeats apparently regressed from approximately 110 in the mother to 44 in her daughter, and the daughter is a carrier of the fragile X mutation based upon the segregation pattern of Xq27 markers flanking FMR1.



Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n

The sequence of a Pst I restriction fragment was determined that demonstrate instability in fragile X syndrome pedigrees. The region of instability was localized to a trinucleotide repeat p(CCG)n.

Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome

expression of the fragile X syndrome appears to result from a two-step mutation as well as a highly localized methylation, and can easily be detected regardless of sex or phenotypic expression.

Spontaneous mutation rates to new length alleles at tandem-repetitive hypervariable loci in human DNA

The spontaneous mutation rate to new length alleles at extremely variable human minisatellites is sufficiently high to be directly measurable in human pedigrees and Germline instability must therefore be taken into account when using hypervariable loci as genetic markers, particularly in pedigree analysis and parenthood testing.

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.

Molecular cloning and analysis of the fragile X region in man.

The fragile X syndrome (FraX), the most common inherited form of mental retardation, has been located to Xq27.3.3 and a contiguous 1.8 Mb region containing the entire fragile X region in YAC and cosmid clones is cloned.

Isolation of sequences that span the fragile X and identification of a fragile X-related CpG island.

A single CpG island was identified in the cloned region between markers DXS463 and DXS465 that appears methylated in mentally retarded fragile X males, but not in nonexpressing male carriers of the mutation nor in normal males.

Fragile X genotype characterized by an unstable region of DNA

This probe provides a means with which to analyze fragile X pedigrees and is a diagnostic reagent for the fragile X genotype.

Proposed mechanism of inheritance and expression of the human fragile-X syndrome of mental retardation.

A mechanism is proposed for the inheritance and expression of the fragile-X-linked syndrome of mental retardation in humans, where a mutation at site Xq27 results in a local block to the reactivation process at a stage where the inactivated X chromosome would normally be reactivated in preparation for oogenesis.