title: Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome.
abstract: The fragile X syndrome, a common cause of inherited mental retardation, is characterized by an unusual mode of inheritance. Phenotypic expression has been linked to abnormal cytosine methylation of a single CpG island, at or very near the fragile site. Probes adjacent to this island detected very localized DNA rearrangements that constituted the fragile X mutations, and whose target was a 550-base pair GC-rich fragment. Normal transmitting males had a 150- to 400-base pair insertion that was inherited by their daughters either unchanged, or with small differences in size. Fragile X-positive individuals in the next generation had much larger fragments that differed among siblings and showed a generally heterogeneous pattern indicating somatic mutation. The mutated allele appeared unmethylated in normal transmitting males, methylated only on the inactive X chromosome in their daughters, and totally methylated in most fragile X males. However, some males had a mosaic pattern. Expression of the fragile X syndrome thus appears to result from a two-step mutation as well as a highly localized methylation. Carriers of the fragile X mutation can easily be detected regardless of sex or phenotypic expression, and rare apparent false negatives may result from genetic heterogeneity or misdiagnosis.
authors.affiliation: Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, Institut de Chimie Biologique, Faculté de Médecine, Strasbourg, France.
authors.forename: I
authors.initials: I
authors.lastname: Oberlé
authors.forename: F
authors.initials: F
authors.lastname: Rousseau
authors.forename: D
authors.initials: D
authors.lastname: Heitz
authors.forename: C
authors.initials: C
authors.lastname: Kretz
authors.forename: D
authors.initials: D
authors.lastname: Devys
authors.forename: A
authors.initials: A
authors.lastname: Hanauer
authors.forename: J
authors.initials: J
authors.lastname: Boué
authors.forename: M F
authors.initials: MF
authors.lastname: Bertheas
authors.forename: J L
authors.initials: JL
authors.lastname: Mandel
mesh_terms: D001482:Base Composition; D004247:DNA / Q000235:genetics*; D005260:Female; D005600:Fragile X Syndrome / Q000235:genetics*; D015321:Gene Rearrangement; D006580:Genetic Carrier Screening; D006801:Humans; D008297:Male; D008745:Methylation; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D015183:Restriction Mapping; D014960:X Chromosome
chemical_list: D004247:DNA