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A single base alteration in the CGG repeat region of FMR1: possible effects on gene expression and phenotype
  1. J Tarleton1,
  2. A Kenneson2,
  3. A K Taylor3,
  4. K Crandall1,
  5. R Fletcher4,
  6. R Casey1,
  7. P S Hart5,
  8. D Hatton6,
  9. G Fisch7,
  10. S T Warren8
  1. 1Fullerton Genetics Center, Mission St Joseph's Health System, 267 McDowell Street, Asheville, NC 28803, USA
  2. 2Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
  3. 3Kimball Genetics Inc, Denver, CO, USA
  4. 4North Carolina Department of Health and Human Services, Asheville, NC, USA
  5. 5Department of Pediatrics, Wake Forest University, Winston-Salem, NC, USA
  6. 6Frank Porter Graham Child Development Center, University of North Carolina, Chapel Hill, NC, USA
  7. 7General Clinical Research Center, Yale University. New Haven, CT, USA
  8. 8Howard Hughes Medical Institute and Departments of Genetics, Biochemistry, and Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
  1. Correspondence to:
 Dr J Tarleton, Fullerton Genetics Center, Mission St Joseph's Health System, 267 McDowell Street, Asheville, NC 28803, USA;
 jack.tarleton{at}msj.org

https://doi.org/10.1136/jmg.39.3.196

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    Fragile X syndrome is characterised by mild to severe mental retardation, minor physical anomalies such as large ears, long facies with a high forehead, joint hyperextensibility, and macro-orchidism, behaviour such as hyperactivity and social avoidance, and speech and developmental delays.1 Trinucleotide repeat (CGG) expansion mutations account for nearly all cases of fragile X syndrome with only a few patients reported with deletions or point mutations in the FMR1 gene.2–4 Expansion beyond approximately 200 repeats (normal range 5-54 repeats), commonly referred to as a “full mutation”, usually results in hypermethylation of the FMR1 promoter region with a concomitant loss of FMR1 transcription and the protein product of the gene, FMRP.5 People with 55-200 repeats have a premutation, which is unstable and prone to expansion when transmitted by females to their offspring. Premutation carriers produce FMRP and typically have few manifestations of the syndrome.

    It is the loss or severe reduction in FMRP that results in the fragile X syndrome.6–8 However, there are numerous reports of subjects with mild phenotypes related to modest FMRP production.9 Such subjects may have learning disabilities but are not retarded (IQ>70), and the milder phenotype appears related to FMRP production arising from transcription of unmethylated alleles. Typically, such patients are cellular mosaics having both full mutations and premutations (termed “full mutation/premutation mosaics”), or having full mutations with varying degrees of methylation (termed “methylation mosaics”). Using a detection technique comprising immunocytochemical staining and counting of lymphocytes expressing FMRP,7 Tassone et al8 identified a significant correlation between FMRP expression and full scale IQ in males with full mutation/premutation mosaicism and methylation mosaicism. These authors observed that the presence of >50% FMRP expressing lymphocytes correlated with non-retarded status (IQ>70). These “high functioning” males, however, displayed some learning disabilities and behavioural manifestations …

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