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GENATLAS PHENOTYPE
last update : 27-09-2017
Symbol FRAXA
Location Xq27.3
HGNC id 3945
Name fragile X syndrome
Other name(s) Martin Bell syndrome
Corresponding gene FMR1
Other symbol(s) FXS
Main clinical features
  • mental retardation
  • subtle dysmorphism, long face with prominent mandible and large ears, facial characteristics such as reduced facial depth, hypoplasticity of the nasal bone-cartilage interface and narrow mid-facial with exaggerating ear prominence (PMID: 23211703))
  • macroorchidism in postpubertal males
  • behavioral abnormalities, due to lack of FMR1 in areas such as the cerebral cortex, amygdala, hippocampus and cerebellum
  • autism is a distinctive subphenotype in FXS with a prevalence range from 25 to 50 percent (PMID: 19441123))
  • anatomical landmark of the disease, is the hyperabundance of immature-looking lengthened dendritic spines (PMID: 21307257))
  • alteration of function and synaptic inputs in the auditory brainstem (PMID: 25679778))
    • Genetic determination sex linked
    Prevalence . incidence in males of 1 in 5161, one of the most frequent cause of inherited mental retardation (PMID: 19804849) . premutatio
    Related entries FXTAS, POF1
    Function/system disorder multisystem/generalized
    mental retardation
    Type MCA/MR
    Gene product
    Name FMRP, a selective RNA-binding protein forming a messenger ribonucleoprotein complex that associates with polyribosomes; FMRP may regulate neuronal translation via microRNAs
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
    repeat expansion   abnormal protein/loss of function expansion of CGG repeat >200, in the 5'untranslated region of the FMR1 gene
    various types     a small number of cases are due to intragenic deletion or point mutation in the FMR1 gene
      fragile site   the fragile site in Xq27.3 is not causal but is a diagnostic marker for the syndrome
    missense     a single missense mutation (I304N) in the second KH domain of FMRP gives rise to a particularly severe case of Fragile X syndrome
    Remark(s)
  • dynamic mutation ; many psychiatric and neurological symptoms of FXS could result from unchecked activation of mGluR5, a metabotropic glutamate receptor
  • overactivation of phosphatases in synapses may be a key deficit in FXS, which affects synaptic translation, transcription, and synaptic receptor regulation
  • having right fronto-striatal dysfunction that is likely an identifiable neuro-phenotypic feature and activation of the left ventrolateral prefrontal cortex during successful response inhibition may reflect compensatory processes (PMID: 17437282))
  • residue Ile304 in KH1-KH2 domain, mutated to Asn is associated with a particularly severe incidence of Fragile X syndrome (Ile304Asn mutation both perturbs the structure and destabilizes the protein) (PMID: 17850748))
  • the upstream terminus of the methylation boundary region exhibits decreased methylation as compared to that of healthy individuals (suggests changes in nucleotide sequence and chromatin structure in the boundary region) (PMID: 19853235))
  • trigger for gene silencing may be local to the repeat itself and perhaps involves a mechanism similar to that involved in the formation of pericentric heterochromatin (PMID: 20843831))
  • defective Programmed cell death (PCD) may contribute to the excess synaptic connections known to exist in FMR1 mutants and could play a role in the behavioral phenotype of children with FRAXA (PMID: 23900139))
    • Genotype/Phenotype correlations
  • normal individuals have 6 to 50 CGG repeats at this site. When the number is more than 200, the FMR1 gene becomes non functional (full mutation), all male patients have mental retardation and half of the females have some degree of mental impairment. Individuals with a repeat number between 50 and 200 are premutation carriers, they do not have mental retardation but females are at risk of having offspring with a full mutation ; premutation carriers may experience premature ovarian failure (POF1) or tremor ataxia syndrome (FXTAS)
  • a single missense mutation (I304N) in the second KH domain of FMRP gives rise to a particularly severe case of Fragile X syndrome