Achondroplasia

Achondroplasia (OMIM #100800) is the most common genetic form of human dwarfism, characterized by disproportionate short stature. Besides long bone abnormalities, it includes head dysmorphology with a prominent forehead, small midface, flattened nasal bridge, and foramen magnum stenosis. Patients often suffer from ear infections, sleep apnea, malocclusion, or hydrocephalus. Current therapy, starting at 2-4 years, improves growth but doesn’t address severe complications from cranial malformations and midface hypoplasia. More info
SHOW MOUSE MODELS

Pathogenic mechanism

Achondroplasia is caused by a gain of function autosomal dominant mutations in the FGFR3 receptor tyrosine kinase, a negative regulator of bone growth. Two pathogenic variants of the FGFR3 gene cause about 99% of cases of achondroplasia. Both variants lead to the replacement of the amino acid glycine to arginine at position 380 (G380R). This genetic change causes the receptor to be overly active, which leads to disturbances in bone growth. Around 80% of cases of achondroplasia occur because of a spontaneous mutation de novo, in the remaining 20% the mutated allele is inherited.

Mouse Models

  • Fgfr3G374RNeoR-fl
  • Fgfr3K650E-EGFP)10Jheb/J