Elevated Levels of FMR1 mRNA in Carrier Males: A New Mechanism of Involvement in the Fragile-X Syndrome

Abstract

Fragile-X syndrome is a trinucleotide-repeat-expansion disorder in which the clinical phenotype is believed to result from transcriptional silencing of the fragile-X mental retardation 1 (FMR1) gene as the number of CGG repeats exceeds ∼200. For premutation alleles (∼55-200 repeats), no abnormalities in FMR1-gene expression have been described, despite growing evidence of clinical involvement in premutation carriers. To address this (apparent) paradox, we have determined, for 16 carrier males (55-192 repeats), the relative levels of leukocyte FMR1 mRNA, by use of automated fluorescence-detection reverse transcriptase-PCR, and the percent of lymphocytes that are immunoreactive for FMR1 protein (FMRP). For some alleles with 1100 repeats, there was a reduction in the number of FMRP-positive cells. Unexpectedly, FMR1 mRNA levels were elevated at least fivefold within this same range. No significant increase in FMR1 mRNA stability was observed in a lymphoblastoid cell line (160 repeats) derived from one of the carrier males, suggesting that the increased message levels are due to an increased rate of transcription. Current results support a mechanism of involvement in premutation carriers, in which reduced translational efficiency is at least partially compensated through increased transcriptional activity. Thus, diminished translational efficiency may be important throughout much of the premutation range, with a mechanistic switch occurring in the full-mutation range as the FMR1 gene is silenced.

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

“…FMR1 mRNA expression levels were measured in peripheral blood leukocytes by quantitative RT-PCR as previously described, 11 and were found to be within the normal range (1.09± 0.16).…”

Intermediate FMR1 alleles and cognitive and/or behavioural phenotypes

“…The lack of FMRP is the direct cause of the FXS phenotype. 3 Expansions of about 55-200 repeats, called premutation alleles, are associated with a significant elevation of FMR1 mRNA levels, 4 and it has been known that carriers of FMR1 premutation have a risk of developing fragile X-associated tremor/ataxia syndrome, a late-onset neurodegenerative disorder. 5,6 Premutation alleles are generally unstable, resulting in an expansion of the CGG repeat sequence when passed from mother to child.…”

Altered hypothalamus–pituitary–adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome

“…While transcription is increased, translation is hampered, resulting in slightly lower FMRP levels in individuals with high CGG-repeat alleles within the PM range (Tassone et al, 2000a;2000b;Kenneson et al, 2001;. Patients with FXTAS usually present with tremor and ataxia, but may develop other neurological symptoms such as Parkinsonism, autonomic dysfunction and peripheral neuropathy and may suffer from cognitive decline including formal dementia.…”