Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers

Hum Mol Genet. 2001 Jul 1;10(14):1449-54. doi: 10.1093/hmg/10.14.1449.


The 5' untranslated CGG repeat in the fragile X mental retardation-1 (FMR1) gene is expanded in families with fragile X syndrome, with more than 200 CGGs resulting in mental retardation due to the absence of the encoded fragile X mental retardation protein (FMRP). Intermediate and premutation alleles, containing between approximately 40 and 200 repeats, express grossly normal FMRP levels and such carriers are widely believed to be non-penetrant, despite continued reports of subtle cognitive/psychosocial impairment and other phenotypes. Using a highly sensitive quantification assay, we demonstrate significantly diminished FMRP levels in carriers, negatively correlated with repeat number. Despite reduced FMRP, these carrier alleles overexpress FMR1, resulting in a positive correlation between repeat number and FMR1 message level. These biochemical deviations associated with intermediate and premutation FMR1 alleles, found in approximately 4% of the population, suggest that the phenotypic spectrum of fragile X syndrome may need to be revisited.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5' Untranslated Regions / genetics
  • Biological Assay / methods
  • Fragile X Mental Retardation Protein
  • Fragile X Syndrome / genetics*
  • Genetic Linkage
  • Heterozygote*
  • Humans
  • Intellectual Disability / genetics
  • Male
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics*
  • RNA-Binding Proteins*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sensitivity and Specificity
  • Statistics as Topic
  • Transcription, Genetic*
  • Trinucleotide Repeats / genetics*


  • 5' Untranslated Regions
  • FMR1 protein, human
  • Nerve Tissue Proteins
  • RNA-Binding Proteins
  • Fragile X Mental Retardation Protein