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GENATLAS PHENOTYPE
last update : 03-12-2011
Symbol ACH
Location 4p16.3
Name achondroplasia
Corresponding gene FGFR3
Main clinical features
  • rhizomelic dwarfism
  • macrocephaly and saddle nose, trident hands
  • dilated lateral ventricles, narrow vertebral canal
    • Genetic determination autosomal dominant
    Prevalence 1/15 000
    Function/system disorder osteo-articular
    Type disease
    Gene product
    Name fibroblast growth factor receptor 3 (FGFR3)
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
    missense   abnormal protein/gain of function mostly G380R, in the TM domain, exceptional G380C
    Remark(s)
  • pathogenesis in achondroplasia cannot be explained simply by a higher dimerization propensity of the mutant FGFR3 TM domain, thus highlighting the importance of the observed slow downregulation in phenotype induction
  • premature synchondrosis closure in the spine and cranial base in human cases of homozygous achondroplasia (PMID: 18923003))
  • with MAPK signaling in chondrocytes, FGFR3 regulate synchondrosis closure, osteoblast differentiation and bone formation, providing novel insights into the developmental mechanisms of spinal canal stenosis, foramen magnum stenosis and midface hypoplasia in achondroplasia (Matsushita 2009)
  • G380R mutation increases FGFR3 phosphorylation in the absence of ligand and at low ligand concentration , and WT/G380R heterodimers form with lower probability than WT/WT homodimers and WT/A391E heterodimers for low FGF1 concentrations (PMID: 21324899))
    • Genotype/Phenotype correlations neomutation on paternal allele in 80 per cent of cases