Molecular Genetics of Achondroplasia


Affecting approximately 250 000 individuals worldwide, achondroplasia (Ach) represents a family of skeletal dysplasias. Although inherited as an autosomal dominant trait, it results most often from a new mutation to unaffected parents. Virtually all patients have the same mutation in the gene that codes for the receptor tyrosine kinase, FGFR3. The mutation exaggerates the receptor's inhibitory functions on bone growth resulting in characteristic clinical features. Similar mutations of FGFR3 cause other members of this disease family. Our understanding of how mutant FGFR3 antagonises bone growth remains incomplete, and delineating the relevant molecular details has proved challenging. Nevertheless, new insights into the FGFR3 biology, that is, downstream FGFR3 signals are modulated by the paracrine hormone CNP, FGFR3 is processed to a fragment with potential nuclear function and FGFR3 signal output is influenced by the molecular chaperone Hsp90, have advanced the field and provided a glimpse into future growth stimulating treatments for Ach.

Key Concepts:

  • Achondroplasia is the prototype of a ‘family’ of human skeletal dysplasias characterised by dwarfism and characteristic craniofacial manifestations.

  • Achondroplasia results from gain of function mutations of the tyrosine kinase‐mediated receptor, FGFR3, which is an important negative regulator of linear bone growth.

  • Although achondroplasia can be inherited as an autosomal dominant trait, it most often results from de‐novo mutations to nonachondroplastic parents. The new mutations display a paternal age effect. Virtually all patients with achondroplasia have the same FGFR3 mutation.

  • Other mutations of FGFR3 that enhance its function cause similar but more or less severe dwarfing conditions, such as thanatophoric dysplasia and hypochondroplasia.

  • FGFR3 acts through ‘signals’ it transmits to the cellular machinery that regulates the proliferation and other behaviours of cells responsible for bone growth – chondrocytes that occupy the growth plates of growing bones. The predominant signalling output involves tyrosine kinase cascades collectively referred to as the MAPK signalling pathway. FGFR3 receptors bearing the achondroplasia mutation exhibit exaggerated MAPK signalling when investigated in both cell culture and mouse models of achondroplasia.

  • The major goal in developing treatments for achondroplasia has been to safely reduce the output of FGFR3 signals to or towards normal. Strategies have ranged from blocking receptor activation to inhibiting FGFR3 tyrosine kinase activity to shortening the survival of actively signalling receptor to antagonising signals downstream of the receptor. These strategies are based on understanding the relevant molecular events. The most promising strategy at present involves administration of the peptide, CNP, which antagonises MAPK signals initiated by FGFR3.

Keywords: skeletal dysplasia; achondroplasia; bone growth; fgfr3; receptor tyrosine kinase

Figure 1.

FGFR3 domain structure. ECD, extracellular domain; ICD, intracellular domain; Ig, immunoglobulin; AB, acid box; TM, transmembrane; KD, kinase domain; Tyr, tyrosine residues. N and C refer to the amino and carboxy termini of the molecule. Modified with permission from Figure , Horton and Degnin, . © Elsevier.

Figure 2.

FGFR3 signal transduction. Binding of ligand to FGFR3 triggers a conformational change that phosphorylates tyrosine residues (T) within the intracellular domain of the receptor, which in turn phosphorylate additional substrate proteins and activate downstream signalling pathways. Modified with permission from Figure , Degnin et al.).

Figure 3.

(a) FGFR3 proteosomal degradation. FGFR3 is stabilised by Hsp90–Cdc37 complex. Addition of Hsp90 inhibitors destabilise this complex resulting in proteosomal degradation of FGFR3. (b) FGFR3 proteolytic cleavage. FGFR3 undergoes a two‐step regulated processing. S1 cleavage results in a membrane anchored C‐terminal domain (CTD) fragment. S2 cleavage within the TM region produces a soluble intracellular domain (sICD) fragment. Figure b modified with permission from Figure 6, Degnin et al., . © American Society for Cell Biology.



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Narayana, Jyoti, and Horton, William A(Jun 2013) Molecular Genetics of Achondroplasia. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024296]