Rare variants in the promoter of the fragile X syndrome gene (FMR1)

doi:10.1006/mcpr.2000.0293

Molecular and Cellular Probes

Volume 14, Issue 2, April 2000, Pages 115-119

https://doi.org/10.1006/mcpr.2000.0293 Get rights and content

Abstract

Fragile X syndrome, the most common form of familial mental retardation, is mainly caused by the expansion of an unstable region of CGG repeats in the 5′ untranslated region of the FMR1 (Fragile X Mental Retardation-1) gene. Molecular tools to detect an abnormal CGG expansion in FMR1 include Southern blot hybridization and PCR amplification. Southern blotting with the StB12.3 probe and Eco RI/Eag I double digestion is widely used as a routine test for fragile X syndrome diagnosis in laboratories around the world. A patient with mental retardation of unknown origin showed absence of digestion for Eag I due to a −149C→G substitution in the CpG island of theFMR1 gene, which destroys that restriction enzyme site. Screening for other changes around that region also detected a −154insGGC in a patient with a phenotype highly suggestive of fragile X syndrome but without CGG expansion. Expression studies did not show any abnormal changes in FMR1 function. In summary, we have identified two different changes (a C to G substitution at −149 and a GGC insertion at −154) in the promoter of the FMR1 gene. These are the first variants described in the promoter of the FMR1 gene.

References (20)

A.J.M.H. Verkerk et al.
Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome
Cell
(1991)
M. Pieretti et al.
Absence of expression of the FMR1 gene in fragile X syndrome
Cell
(1991)
R. Willemsen et al.
Rapid antibody test for fragile X syndrome
Lancet
(1995)
G. Turner et al.
Prevalence of fragile X syndrome
American Journal of Human Genetics
(1996)
D. Devys et al.
The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation
Nature Genetics
(1993)
S.T. Warren et al.
Advances in molecular analysis of fragile X syndrome
JAMA
(1994)
M. Milà et al.
Molecular analysis of the (CGG)n expansion in the FMR1 gene in 59 Spanish fragile X syndrome families
Human Genetics
(1994)
M. Milà et al.
Screening for FMR1 and FMR2 mutations in 222 individuals from Spanish special schools: identification of a case of FRAXE-associated mental retardation
Human Genetics
(1997)
S. Sherman
The high prevalence of fragile X premutation carrier females: is this frequency unique to the French Canadian population?
American Journal of Human Genetics
(1995)
K. De Boulle et al.
A point mutation in the FMR1 gene associated with fragile X mental retardation
Nature Genetics
(1993)

There are more references available in the full text version of this article.

Cited by (15)

The -413C > G substitution in the promoter of the FMR1 gene is not associated with the fragile X syndrome phenotype
2010, Molecular and Cellular Probes
Citation Excerpt :
The same variant was described by Milà and coworkers [6], and reported as -149C > G (numbered according to the FMR1 transcription start site). They found the -413C > G substitution in a patient with mental retardation of unknown origin, but their results were not conclusive about the pathogenic role of the substitution because neither family data were available nor expression studies were performed [6]. We failed to detect the variant in a sample of normal individuals.
Most common inherited form of intellectual disability, fragile X syndrome is associated to an expansion of greater than 200 CGG repeats in the 5′ untranslated region of the FMR1 gene on the X chromosome which causes transcriptional silencing and deficiency of the encoded protein FMRP. Molecular diagnosis is performed through a combination of PCR to identify fewer than 100–150 repeats and of Southern blot analysis to identify longer alleles and the methylation status of the FMR1 promoter. We present a family with one patient with mild mental retardation who showed an atypical profile at Southern analysis due to the -413C > G transversion located in the FMR1 promoter which had been described as possibly associated with mental retardation. We demonstrated this variant in other four family members along three generations, including the maternal grandfather who did not manifest any pathological feature. Though the -413C > G substitution was not found in a large control series, these findings allowed to exclude its role in determining the disease phenotype.
The Fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses
2003, Cell
The Fragile X syndrome, which results from the absence of functional FMRP protein, is the most common heritable form of mental retardation. Here, we show that FMRP acts as a translational repressor of specific mRNAs at synapses. Interestingly, FMRP associates not only with these target mRNAs, but also with the dendritic, non-translatable RNA BC1. Blocking of BC1 inhibits the interaction of FMRP with its target mRNAs. Furthermore, BC1 binds directly to FMRP and can also associate, in the absence of any protein, with the mRNAs regulated by FMRP. This suggests a mechanism where BC1 could determine the specificity of FMRP function by linking the regulated mRNAs and FMRP. Thus, when FMRP is not present, loss of translational repression of specific mRNAs at synapses could result in synaptic dysfunction phenotype of Fragile X patients.
EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders
2015, European Journal of Human Genetics
The FMRP regulon: From targets to disease convergence
2013, Frontiers in Neuroscience
Molecular and cellular aspects of mental retardation in the Fragile X syndrome: From gene mutation/s to spine dysmorphogenesis
2012, Advances in Experimental Medicine and Biology
Clinical utility gene card for: Fragile X mental retardation syndrome, fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency
2011, European Journal of Human Genetics

View all citing articles on Scopus

^f1: Author to whom all correspondence should be addressed at: Servei de Genètica, Hospital Clı́nic, Villarroel 170, 08036 Barcelona, Spain. Tel: +34 93 2275400 (ext. 2784); Fax: +34 93 4515272; E-mail: [email protected]

View full text

Regular ArticleRare variants in the promoter of the fragile X syndrome gene (FMR1)

Abstract

Cell

Cell

Lancet

Prevalence of fragile X syndrome

American Journal of Human Genetics

The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation

Nature Genetics

Advances in molecular analysis of fragile X syndrome

JAMA

Molecular analysis of the (CGG)n expansion in the FMR1 gene in 59 Spanish fragile X syndrome families

Human Genetics

Screening for FMR1 and FMR2 mutations in 222 individuals from Spanish special schools: identification of a case of FRAXE-associated mental retardation

Human Genetics

The high prevalence of fragile X premutation carrier females: is this frequency unique to the French Canadian population?

American Journal of Human Genetics

A point mutation in the FMR1 gene associated with fragile X mental retardation

Nature Genetics

Regular Article
Rare variants in the promoter of the fragile X syndrome gene (FMR1)