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