SCIENTIFIC BACKGROUND

FGFR3

Achondroplasia is an autosomal-dominantly inherited, disproportionate short stature syndrome, which is mainly characterized by rhizomelic shortening of the limbs. The prevalence of the disease is reported to be around one in 26,000-28,000 live births. The cause is thought to be gain-of-function variants in the fibroblast growth factor receptor 3 (FGFR3) gene, which lead to changes in FGF-dependent calcium signal transduction. Up to 20% of cases are familial, the vast majority of cases are due to new mutations in the FGFR3 gene (presumably germline mosaics of the paternal germ cells or spontaneous mutations during early fetal development).

 

The classic cases of achondroplasia show changes in codon 380 of the FGFR3 gene, which lead to the replacement of glycine by arginine. The resulting dysregulation of enchondral ossification ultimately leads to disproportionate short stature. The mutation rate of the nucleic acid localized in codon 380 in position 1138 is increased by a factor of 1,000 compared to the average mutation rate in the human genome and is therefore one of the regions with the highest mutation rate of all. The spontaneous mutation rate in these regions is strongly dependent on the age of the father and is reported to be about 10 times higher in 50-year-old men compared to 20-year-olds (paternal age effect).

 

Since mild cases of achondroplasia caused by Gly380Arg and severe cases of hypochondroplasia caused by Asn540Lys are clinically very similar and can therefore be easily confused, both mutations are examined in stage I of the diagnostic process.

 

References

Pereira 2019, Pediatr Rev 40:316 / Daugherty 2017, Neonatal Netw 36:337 / Klag et Horton 2015, Hum Mol Genet pii:ddv419 / Laederich et al. 2012, Expert Rev Mol Med 14:e11 / Wright et Irving 2011, Arch Dis Child 97:129 / Baujat et al. 2008, Best Pract Res Clin Rheumatol 22:3 / Vajo et al. 2000, Endocr Rev 21:23 / Witkowski et al. 1999, Lexikon der Syndrome und Fehlbildungen, 6. Auflage / Shiang et al. 1994, Cell 78:335 / Rousseau et al. 1994, Nature 371:252

GENES

FGFR3
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