Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1

doi:10.1016/S1474-4422(06)70676-7

The Lancet Neurology

Volume 6, Issue 1, January 2007, Pages 45-55

https://doi.org/10.1016/S1474-4422(06)70676-7 Get rights and content

Summary

Recent advances in our understanding of the clinical and molecular features of the fragile-X mental-retardation 1 gene, FMR1, highlight the importance of single-gene disorders. 15 years after its discovery, FMR1 continues to reveal new and unexpected clinical presentations and molecular mechanisms. Loss of function of FMR1 is a model for neurodevelopmental and behavioural disorders, including mental retardation, autism, anxiety, and mood instability. In addition, overexpression and CNS toxicity of FMR1 mRNA causes a late-onset neurodegenerative disorder, the fragile-X-associated tremor/ataxia syndrome (FXTAS). A similar mechanism is probably involved in premature ovarian failure, which affects up to 20% of female carriers of an altered FMR1 gene.

Introduction

This review covers the clinical, molecular, and neurobiological features of fragile-X syndrome, the most common cause of inherited mental retardation,¹ as well as new prospects for therapeutic approaches. The fragile-X story illustrates the growing interest in non-coding RNA in human genetics. Researchers first focused on the protein-coding role of FMR1, relating fragile-X syndrome to the lack of the protein FMRP.1, 2, 3 Subsequently, premature ovarian failure⁴ and fragile-X-associated tremor/ataxia syndrome (FXTAS)5, 6 have been linked to the untranslated region of the FMR1 transcript.

The 5' untranslated region of FMR1 contains a CGG repeat sequence7, 8 that is stably transmitted in the normal range (5–44 repeats). Expansion of this CGG repeat is associated with changes in the amounts of FMR1 mRNA and protein and with varied phenotypes. Full mutation alleles (>200 repeats) are associated with gene methylation and transcriptional silencing, which cause fragile-X syndrome. Rarely, the syndrome can result from mutations not involving expansion of the CGG repeat region: several patients with the disorder have deletions of FMR1 or its promoter.⁹ Premutation alleles (55–200 CGG repeats¹⁰) are unstable and may expand to full mutation alleles when transmitted maternally. Expansions of 45–54 repeats (grey-zone expansions) are only mildly unstable and require at least two generations before evolving into a full mutation.

Section snippets

Aetiology: low expression of FMRP

Cognitive and behavioural problems, facial dysmorphism, connective-tissue anomalies, and macro-orchidism are classic symptoms of fragile-X syndrome (table 14, 11, 12, 13, 14). Macro-orchidism, although not specific for fragile-X syndrome, is the most consistent finding, present in 90% of boys by age 14 years. Mild increases of gonadotropin concentrations suggest hypothalamopituitary dysregulation.¹¹ Some individuals with fragile-X syndrome may at first be suspected to have Prader-Willi

FMR1 premutations: a common allele

Originally, the premutation range (55–200 CGG repeats) was defined from the perspective of risk of transmitting a full mutation allele from a (premutation) carrier female to her progeny, since alleles in this size range are unstable upon maternal transmission.⁵⁴ Thus, the original definition of the premutation was not based on a clinical phenotype of the carrier. One could predict, therefore, that the range of allele sizes later found to be associated with clinical pathology (ie,

FMR1 screening and genetic counseling

As our knowledge of FMR1-related phenotypes expands, genetic counselling for families of carriers of fragile-X alleles becomes increasingly complex. Diagnosis of an individual with a full mutation or a premutation has consequences for many family members. Clinicians should inform their patients that women in their family might be at risk of having a child with fragile-X syndrome and refer them to a geneticist or genetic counsellor. The possibility of premature ovarian failure should be

Search strategy and selection criteria

References for this review were identified by searches of PubMed between 1999 and December 2006. Older references are cited when essential to the understanding of ongoing research. Articles were also identified by searches of the authors' files. The search terms “fragile X”, “premutation”, “FXTAS”, and “premature ovarian failure” were used. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the topics covered

Glossary

Untranslated region (UTR): A region that is transcribed and present in mRNA but not translated into protein and located either upstream (5'UTR) or downstream (3'UTR) of a protein coding gene.
CGG repeat: Sequence of nucleotides CGG tandemly repeated, present in the 5'UTR promoter of FMR1—normal size is <55 CGG repeats.
Full mutation: >200 CGG repeats. An allele carrying these repeats causes fragile-X syndrome.
Gene methylation: Addition of methyl groups at certain sites on a gene leading to silencing of

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ReviewFragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1

Summary

Introduction

Section snippets

Aetiology: low expression of FMRP

FMR1 premutations: a common allele

FMR1 screening and genetic counseling

Search strategy and selection criteria

Glossary

Am J Hum Genet

Cell

Genet Med

J Am Acad Child Adolesc Psychiatry

Lancet Neurol

Cell

Cell

Curr Biol

Neuron

Trends Neurosci

Neuron

Neuropharmacology

Am J Hum Genet

Am J Hum Genet

Brain Cogn

Am J Hum Genet

Eur J Obstet Gynecol Reprod Biol

J Neurol Sci

Am J Hum Genet

Biochem Mol Med

Neuron

Behav Brain Res

Neuropsychologia

FMRP expression as a potential prognostic indicator in fragile X syndrome

Am J Med Genet

Genotype, molecular phenotype, and cognitive phenotype: correlations in fragile X syndrome

Am J Med Genet

Phenotypic variation and FMRP levels in fragile X

Ment Retard Dev Disabil Res Rev

Association of FMR1 repeat size with ovarian dysfunction

Hum Reprod

Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X

Neurology

Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome

Science

Fragile X syndrome without CCG amplification has an FMR1 deletion

Nat Genet

The physical and behavioral phenotype

Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population

JAMA

Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS)

Brain

Epilepsy in fragile X syndrome

Dev Med Child Neurol

Profile of cognitive functioning in women with the fragile X mutation

Neuropsychology

Functional brain activation during arithmetic processing in females with fragile X Syndrome is related to FMR1 protein expression

Hum Brain Mapp

The neuroanatomy and neuroendocrinology of fragile X syndrome

Ment Retard Dev Disabil Res Rev

Frontostriatal deficits in fragile X syndrome: relation to FMR1 gene expression

Proc Natl Acad Sci USA

The influence of environmental and genetic factors on behavior problems and autistic symptoms in boys and girls with fragile X syndrome

Pediatrics

Autistic behavior in children with fragile X syndrome: Prevalence, stability, and the impact of FMRP

Am J Med Genet A

Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors

Am J Med Genet A

The behavioral phenotype in fragile X: symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmental disorders

J Dev Behav Pediatr

Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X

Neurosci BioBehav Rev

Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice

Mol Psychiatry

Electrodermal responses to sensory stimuli in individuals with fragile X syndrome: a preliminary report

Am J Med Genet

Cardiovascular indices of physiological arousal in boys with fragile X syndrome

Dev Psychobiol

Here's looking at you kid: neural systems underlying face and gaze processing in fragile X syndrome

Arch Gen Psychiatry

Epilepsy and EEG findings in males with fragile X syndrome

Review
Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1