Transcription of the FMR1 gene in individuals with fragile X syndrome

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Abstract

Fragile X syndrome generally arises as a consequence of a large expansion of a CGG trinucleotide repeat element that is located in the GC-rich promoter region of the fragile X mental retardation gene (FMR1). In the conventional model for fragile X, clinical involvement arises as a consequence of silencing of the FMR1 gene, with the attendant loss of FMR1 protein (FMRP). However, it has recently been demonstrated that most males with large premutation alleles (100-200 repeats), or with unmethylated full mutation alleles, have FMR1 mRNA levels that are higher than normal, despite reduced levels of FMRP. In the current work, we extend and confirm these observations using quantitative (fluorescent) reverse transcription polymerase chain reaction on larger sample populations, establishing that even for smaller premutation alleles (55-100 repeats) the mRNA levels are significantly elevated (mean 2.1-fold elevation; P = 3.9 × 10 -3), relative to normal controls. Thus, an abnormal molecular phenotype is established close to the upper end of the normal range. We also demonstrate that the levels of FMR1 mRNA are elevated in females with premutation alleles; however, the mRNA levels are more varied than in the males, and are attenuated in a manner that is consistent with the fraction of normal alleles that are active in any given individual. Finally, we demonstrate that in lymphoblastoid cells derived from a patient with a severe form of fragile X caused by a point mutation in the second KH domain of the gene, but with a normal CGG element (25 repeats), the FMR1 mRNA level is normal. Thus, although models in which FMRP level (or level of function) modulates transcriptional activity remain viable, other explanations for the elevated message levels, including direct (cis) effects of the CGG element on transcription, must also be considered. Am. J. Med. Genet. (Semin. Med. Genet.) 97:195-203, 2000.

Original languageEnglish (US)
Pages (from-to)195-203
Number of pages9
JournalAmerican Journal of Medical Genetics - Seminars in Medical Genetics
Volume97
Issue number3
DOIs
StatePublished - 2000

Fingerprint

Fragile X Syndrome
Alleles
Messenger RNA
Viverridae
Genes
GC Rich Sequence
Trinucleotide Repeats
Proteins
Gene Silencing
Point Mutation
Genetic Promoter Regions
Intellectual Disability
Reverse Transcription
Reference Values
Phenotype
Polymerase Chain Reaction
Mutation
Population

Keywords

  • Autism
  • Gene silencing
  • Mental retardation
  • RT-PCR
  • Transcription

ASJC Scopus subject areas

  • Genetics(clinical)
  • Neuropsychology and Physiological Psychology
  • Neuroscience(all)

Cite this

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title = "Transcription of the FMR1 gene in individuals with fragile X syndrome",
abstract = "Fragile X syndrome generally arises as a consequence of a large expansion of a CGG trinucleotide repeat element that is located in the GC-rich promoter region of the fragile X mental retardation gene (FMR1). In the conventional model for fragile X, clinical involvement arises as a consequence of silencing of the FMR1 gene, with the attendant loss of FMR1 protein (FMRP). However, it has recently been demonstrated that most males with large premutation alleles (100-200 repeats), or with unmethylated full mutation alleles, have FMR1 mRNA levels that are higher than normal, despite reduced levels of FMRP. In the current work, we extend and confirm these observations using quantitative (fluorescent) reverse transcription polymerase chain reaction on larger sample populations, establishing that even for smaller premutation alleles (55-100 repeats) the mRNA levels are significantly elevated (mean 2.1-fold elevation; P = 3.9 × 10 -3), relative to normal controls. Thus, an abnormal molecular phenotype is established close to the upper end of the normal range. We also demonstrate that the levels of FMR1 mRNA are elevated in females with premutation alleles; however, the mRNA levels are more varied than in the males, and are attenuated in a manner that is consistent with the fraction of normal alleles that are active in any given individual. Finally, we demonstrate that in lymphoblastoid cells derived from a patient with a severe form of fragile X caused by a point mutation in the second KH domain of the gene, but with a normal CGG element (25 repeats), the FMR1 mRNA level is normal. Thus, although models in which FMRP level (or level of function) modulates transcriptional activity remain viable, other explanations for the elevated message levels, including direct (cis) effects of the CGG element on transcription, must also be considered. Am. J. Med. Genet. (Semin. Med. Genet.) 97:195-203, 2000.",
keywords = "Autism, Gene silencing, Mental retardation, RT-PCR, Transcription",
author = "Flora Tassone and Hagerman, {Randi J} and Chamberlain, {Winston D.} and Hagerman, {Paul J}",
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T1 - Transcription of the FMR1 gene in individuals with fragile X syndrome

AU - Tassone, Flora

AU - Hagerman, Randi J

AU - Chamberlain, Winston D.

AU - Hagerman, Paul J

PY - 2000

Y1 - 2000

N2 - Fragile X syndrome generally arises as a consequence of a large expansion of a CGG trinucleotide repeat element that is located in the GC-rich promoter region of the fragile X mental retardation gene (FMR1). In the conventional model for fragile X, clinical involvement arises as a consequence of silencing of the FMR1 gene, with the attendant loss of FMR1 protein (FMRP). However, it has recently been demonstrated that most males with large premutation alleles (100-200 repeats), or with unmethylated full mutation alleles, have FMR1 mRNA levels that are higher than normal, despite reduced levels of FMRP. In the current work, we extend and confirm these observations using quantitative (fluorescent) reverse transcription polymerase chain reaction on larger sample populations, establishing that even for smaller premutation alleles (55-100 repeats) the mRNA levels are significantly elevated (mean 2.1-fold elevation; P = 3.9 × 10 -3), relative to normal controls. Thus, an abnormal molecular phenotype is established close to the upper end of the normal range. We also demonstrate that the levels of FMR1 mRNA are elevated in females with premutation alleles; however, the mRNA levels are more varied than in the males, and are attenuated in a manner that is consistent with the fraction of normal alleles that are active in any given individual. Finally, we demonstrate that in lymphoblastoid cells derived from a patient with a severe form of fragile X caused by a point mutation in the second KH domain of the gene, but with a normal CGG element (25 repeats), the FMR1 mRNA level is normal. Thus, although models in which FMRP level (or level of function) modulates transcriptional activity remain viable, other explanations for the elevated message levels, including direct (cis) effects of the CGG element on transcription, must also be considered. Am. J. Med. Genet. (Semin. Med. Genet.) 97:195-203, 2000.

AB - Fragile X syndrome generally arises as a consequence of a large expansion of a CGG trinucleotide repeat element that is located in the GC-rich promoter region of the fragile X mental retardation gene (FMR1). In the conventional model for fragile X, clinical involvement arises as a consequence of silencing of the FMR1 gene, with the attendant loss of FMR1 protein (FMRP). However, it has recently been demonstrated that most males with large premutation alleles (100-200 repeats), or with unmethylated full mutation alleles, have FMR1 mRNA levels that are higher than normal, despite reduced levels of FMRP. In the current work, we extend and confirm these observations using quantitative (fluorescent) reverse transcription polymerase chain reaction on larger sample populations, establishing that even for smaller premutation alleles (55-100 repeats) the mRNA levels are significantly elevated (mean 2.1-fold elevation; P = 3.9 × 10 -3), relative to normal controls. Thus, an abnormal molecular phenotype is established close to the upper end of the normal range. We also demonstrate that the levels of FMR1 mRNA are elevated in females with premutation alleles; however, the mRNA levels are more varied than in the males, and are attenuated in a manner that is consistent with the fraction of normal alleles that are active in any given individual. Finally, we demonstrate that in lymphoblastoid cells derived from a patient with a severe form of fragile X caused by a point mutation in the second KH domain of the gene, but with a normal CGG element (25 repeats), the FMR1 mRNA level is normal. Thus, although models in which FMRP level (or level of function) modulates transcriptional activity remain viable, other explanations for the elevated message levels, including direct (cis) effects of the CGG element on transcription, must also be considered. Am. J. Med. Genet. (Semin. Med. Genet.) 97:195-203, 2000.

KW - Autism

KW - Gene silencing

KW - Mental retardation

KW - RT-PCR

KW - Transcription

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