Molecular analysis of mutations in the gene FMR-1 segregating in fragile X families

Hum Genet. 1993 Nov;92(5):491-8. doi: 10.1007/BF00216457.


Molecular genetic analysis of the transmission of mutations in 73 families with fragile X (one of the largest samples evaluated so far) has confirmed previous hypotheses that the fragile X syndrome results from two consecutive mutational steps, designated "premutation" and "full fragile X mutation". These mutations give rise to expansions of restriction fragments, most probably by amplification of the FMR-1 CGG repeat. Premutations are identified by small expansions that apparently have no effect on either the clinical or the cellular phenotype. Full mutations are reflected by large expansions and hypermethylation of the expanded gene region. All males showing large expansions were affected. Individuals with full mutations also expressed the fragile X, with only one exception. An affected "mosaic" male, showing a predominance of premutated fragments in his leukocytes, was shown to be fragile-X-negative on different occasions. About 50% of heterozygotes with full mutations were reported by clinicians to be mentally retarded. Conversion of the premutation to the full mutation may occur at oogenesis, as previously suggested, or after formation of a zygote at an early transitional stage in development when the CGG repeat behaves as a mitotically unstable element on maternally derived/imprinted X chromosomes carrying a premutation of sufficient repeat length.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • DNA / metabolism
  • DNA Mutational Analysis
  • Embryonic and Fetal Development
  • Female
  • Fragile X Mental Retardation Protein
  • Fragile X Syndrome / genetics*
  • Gene Conversion
  • Gene Expression Regulation
  • Genes, Recessive
  • Heterozygote
  • Humans
  • Male
  • Methylation
  • Mosaicism
  • Mothers
  • Mutagenesis
  • Mutation / genetics*
  • Nerve Tissue Proteins / genetics
  • Pedigree
  • Phenotype
  • Polymorphism, Restriction Fragment Length
  • RNA-Binding Proteins*
  • Repetitive Sequences, Nucleic Acid*
  • Restriction Mapping
  • Zygote


  • FMR1 protein, human
  • Nerve Tissue Proteins
  • RNA-Binding Proteins
  • Fragile X Mental Retardation Protein
  • DNA