The effect of pre-mutation of X chromosome CGG trinucleotide repeats on brain anatomy

Caroline J. Moore, Eileen M. Daly, Flora Tassone, Carolyn Tysoe, Nicole Schmitz, Virginia Ng, Xavier Chitnis, Philip McGuire, John Suckling, Kay E. Davies, Randi J Hagerman, Paul J Hagerman, Kieran C. Murphy, Declan G M Murphy

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Expanded trinucleotide repeats are associated with several neuropsychiatric disorders, including fragile X syndrome (FraX) which is the most common inherited form of mental retardation. It is currently thought that FraX results from having >200 CGG trinucleotide repeats, with consequent methylation of the fragile X mental retardation gene (FMR1) and loss of FMR1 protein (FMRP). Pre-mutation carriers of FraX (with 55-200 CGG trinucleotide repeats) were originally considered unaffected, although recent studies challenge this view. However, there are few studies on the effect of premutation trinucleotide repeat expansion on the male human brain using quantitative MRI. Also the results of prior investigations may be confounded because people were selected on the basis of clinical and neurological features, and not genetic phenotype. We compared the brain anatomy of 20 adult male premutation members of known FraX families with 20 healthy male controls. The two groups did not differ significantly in age, intelligence quotient (IQ) or handedness. We also investigated whether any observed effects were associated with: (i) ageing; (ii) expansion of pre-mutation CGG trinucleotide repeats; (iii) reduction in the percentage of lymphocytes staining with anti-FMRP antibodies [%FMRP(+) lymphocytes]; and (iv) elevation of FMR1 mRNA levels. Male pre-mutation carriers of FraX, compared with matched controls, had significantly less voxel density in several brain regions, including the cerebellum, amygdalo-hippocampal complex and thalamus. Within pre-mutation carriers of FraX, ageing, increases in the number of CGG trinucleotide repeats and decreases in %FMRP(+) lymphocytes were associated with decreasing voxel density of regions previously identified as decreased relative to controls. Regional grey and white matter density is significantly affected in male pre-mutation carriers of FraX recruited on the basis of genetic, not clinical, phenotype. The association of voxel density reduction and ageing is consistent with observations of a subgroup of older pre-mutation males who present with cognitive decline. Moreover, our findings suggest, for the first time, an association between voxel density reduction and genetic variation in FraX.

Original languageEnglish (US)
Pages (from-to)2672-2681
Number of pages10
JournalBrain
Volume127
Issue number12
DOIs
StatePublished - Dec 2004

Fingerprint

Trinucleotide Repeats
Fragile X Syndrome
X Chromosome
Anatomy
Mutation
Brain
Trinucleotide Repeat Expansion
Lymphocytes
Intellectual Disability
Proteins
Phenotype
Functional Laterality
Thalamus
Intelligence
Cerebellum
Methylation
Staining and Labeling
Messenger RNA
Antibodies

Keywords

  • Brain, MRI
  • Fragile X syndrome
  • Pre-mutation
  • Trinucleotide repeats
  • X chromosome

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Moore, C. J., Daly, E. M., Tassone, F., Tysoe, C., Schmitz, N., Ng, V., ... Murphy, D. G. M. (2004). The effect of pre-mutation of X chromosome CGG trinucleotide repeats on brain anatomy. Brain, 127(12), 2672-2681. https://doi.org/10.1093/brain/awh256

The effect of pre-mutation of X chromosome CGG trinucleotide repeats on brain anatomy. / Moore, Caroline J.; Daly, Eileen M.; Tassone, Flora; Tysoe, Carolyn; Schmitz, Nicole; Ng, Virginia; Chitnis, Xavier; McGuire, Philip; Suckling, John; Davies, Kay E.; Hagerman, Randi J; Hagerman, Paul J; Murphy, Kieran C.; Murphy, Declan G M.

In: Brain, Vol. 127, No. 12, 12.2004, p. 2672-2681.

Research output: Contribution to journalArticle

Moore, CJ, Daly, EM, Tassone, F, Tysoe, C, Schmitz, N, Ng, V, Chitnis, X, McGuire, P, Suckling, J, Davies, KE, Hagerman, RJ, Hagerman, PJ, Murphy, KC & Murphy, DGM 2004, 'The effect of pre-mutation of X chromosome CGG trinucleotide repeats on brain anatomy', Brain, vol. 127, no. 12, pp. 2672-2681. https://doi.org/10.1093/brain/awh256
Moore, Caroline J. ; Daly, Eileen M. ; Tassone, Flora ; Tysoe, Carolyn ; Schmitz, Nicole ; Ng, Virginia ; Chitnis, Xavier ; McGuire, Philip ; Suckling, John ; Davies, Kay E. ; Hagerman, Randi J ; Hagerman, Paul J ; Murphy, Kieran C. ; Murphy, Declan G M. / The effect of pre-mutation of X chromosome CGG trinucleotide repeats on brain anatomy. In: Brain. 2004 ; Vol. 127, No. 12. pp. 2672-2681.
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abstract = "Expanded trinucleotide repeats are associated with several neuropsychiatric disorders, including fragile X syndrome (FraX) which is the most common inherited form of mental retardation. It is currently thought that FraX results from having >200 CGG trinucleotide repeats, with consequent methylation of the fragile X mental retardation gene (FMR1) and loss of FMR1 protein (FMRP). Pre-mutation carriers of FraX (with 55-200 CGG trinucleotide repeats) were originally considered unaffected, although recent studies challenge this view. However, there are few studies on the effect of premutation trinucleotide repeat expansion on the male human brain using quantitative MRI. Also the results of prior investigations may be confounded because people were selected on the basis of clinical and neurological features, and not genetic phenotype. We compared the brain anatomy of 20 adult male premutation members of known FraX families with 20 healthy male controls. The two groups did not differ significantly in age, intelligence quotient (IQ) or handedness. We also investigated whether any observed effects were associated with: (i) ageing; (ii) expansion of pre-mutation CGG trinucleotide repeats; (iii) reduction in the percentage of lymphocytes staining with anti-FMRP antibodies [{\%}FMRP(+) lymphocytes]; and (iv) elevation of FMR1 mRNA levels. Male pre-mutation carriers of FraX, compared with matched controls, had significantly less voxel density in several brain regions, including the cerebellum, amygdalo-hippocampal complex and thalamus. Within pre-mutation carriers of FraX, ageing, increases in the number of CGG trinucleotide repeats and decreases in {\%}FMRP(+) lymphocytes were associated with decreasing voxel density of regions previously identified as decreased relative to controls. Regional grey and white matter density is significantly affected in male pre-mutation carriers of FraX recruited on the basis of genetic, not clinical, phenotype. The association of voxel density reduction and ageing is consistent with observations of a subgroup of older pre-mutation males who present with cognitive decline. Moreover, our findings suggest, for the first time, an association between voxel density reduction and genetic variation in FraX.",
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