title: Transcript levels of the intermediate size or grey zone fragile X mental retardation 1 alleles are raised, and correlate with the number of CGG repeats.
abstract: BACKGROUND
  Grey zone or intermediate alleles are one of the three recognised classes of the X-linked fragile X mental retardation 1 (FMR1) gene showing intergenerational instability. These classes are defined according to the number of CGG repeats in the FMR1 5'-untranslated region. Although large CGG expansions (>200 repeats) cause a neurodevelopmental anomaly through silencing of the gene, resulting in a deficit of FMR1 specific protein, smaller expansions (approximately 55-200 repeats) are associated with an increased transcription and late-onset specific phenotypes. Those alleles with a CGG repeat number ranging between approximately 41 and 55 are relatively poorly defined with regard to both transcriptional and translational activity, and also potential phenotypic effects.
  
  
  RESULTS
  Based on a sample of 33 males carrying FMR1 alleles within the grey zone range, defined here as 41-60 CGGs, we show an increased transcriptional activity relative to that seen in common alleles (5-40 CGGS). This is the first study to report a significant relationship between FMR1 mRNA levels and CGG repeat number within the grey zone range (p<0.001). From a piecewise linear regression model, the threshold for onset of the increase in mRNA levels as a function of CGG repeat size has been determined at approximately 39 repeats (standard error (SE) 3.24), and that for the reduction in the rate of this increase at approximately 54 repeats (SE 4.27).
  
  
  CONCLUSIONS
  The ambiguities associated with the definition and transcription dynamics of the FMR1 gene within the grey zone range are dealt with. There may be specific phenotypes associated with the toxic "gain-of-function" effect of raised mRNA.
authors.affiliation: School of Psychological Science, La Trobe University, Melbourne, Victoria 3086, Australia. d.loesch@latrobe.edu.au
authors.forename: Danuta Z
authors.initials: DZ
authors.lastname: Loesch
authors.forename: Quang M
authors.initials: QM
authors.lastname: Bui
authors.forename: Richard M
authors.initials: RM
authors.lastname: Huggins
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mitchell
authors.forename: Randi J
authors.initials: RJ
authors.lastname: Hagerman
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000483:Alleles; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics*; D006801:Humans; D016014:Linear Models; D008297:Male; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D019680:Trinucleotide Repeat Expansion; D015854:Up-Regulation
chemical_list: D020121:5' Untranslated Regions; D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; C497683:FMR1 protein, human