Achondroplasia (ACH) [Q77.4]
Dr. rer. nat. Christoph Marschall, Dipl.-Biol. Christine Schack,
Dipl.-Biol. Christina Sofeso
Achondroplasia is an autosomal dominant disorder of bone growth that is characterized by disproportionately short stature with rhizomelic shortening of the limbs. The incidence is estimated to be 1 in 20,000. The disorder is caused by mutations in the fibroblast growth factor receptor 3 (FGFR3 gene) that lead to changes in the FGF-dependent calcium signal transduction. Up to 20% of the cases are familial, but the majority of cases are caused by de novo mutations in the FGFR3 gene (presumably germline mosaicisms in the paternal germ cells, or spontaneous mutations in early fetal development).
The classic cases of achondroplasia exhibit mutations in codon 380 of the FGFR3 gene, which lead to a substitution of glycine by arginine. The resulting dysfunctional regulation of endochondral ossification eventually leads to disproportionately short stature. The mutation rate of the nucleic acid at position 1,138, localized in codon 380, is elevated by a factor of 1,000 compared to the average mutation rate in the human genome and, thus, belongs to the regions with one of the highest mutation rates. The spontaneous mutation rate in this region is strongly affected by the age of the father, and is given as 10 fold higher at a paternal age of 40 than at 20 (paternal age effect).