Achondroplasia Research Paper

Achondroplasia
In humans achondroplasia is the most common form of non-lethal skeletal dysplasia (short limb dwarfism), affecting over 250,000 people worldwide. The incidence is approximately one in 10,000-30,000 live births. (1-7) Achondroplasia is characterised by short stature (average height of 120-132cm (2,3)) with disproportionately shorter proximal limb bones, a long trunk with a narrow thorax, macrocephaly with frontal bossing and mid face hyperplasia. (1-4) People with achondroplasia also have short broad hands with trident like appearance of the fingers, thoraco-lumbar kyphosis and bow leg deformity due to a faster growth rate of the fibula relative to the tibia. There are also many more pathological features due to the varied effects
of an increase in fibroblast growth factor receptor 3 activation on the cartilaginous growth plates in the growing skeleton. (1,3,4)

Figure 1: Achondroplasia phenotype at different ages (from reference 1)

Achondroplasia is an autosomal dominant trait and has been mapped to chromosome 4p16.3, where heterozygous mutations have been identified in the FGFR3 (fibroblast growth factor receptor 3) gene. (1) Homozygous mutations are perinatally lethal as this genotype results in severe respiratory compromise due to the increased severity of skeletal dysplasia in comparison to the heterozygote. (1,4) Therefore all people with achondroplasia are heterozygous for the FGFR3 mutation. A strong correlation between genotype and phenotype has been observed and the extent of the gain in function caused by mutation of FGFR3 correlates with the severity of the clinical phenotype. (1) Achondroplasia has a high de-novo mutation rate consequently around 80% of cases are as a result of new mutations, most likely to be of paternal origin. (1,3,4) The main contributing factor to the high de-novo mutation rate is an increase in paternal age, this is predicted to be due to the fact that sperm containing the FGFR3 mutations associated with achondroplasia have a selective growth advantage, thus are more common with increased age. (1,2,4)

The gene affected by the mutation encodes fibroblast growth factor receptor 3 (FGFR3) and around 95% of people with achondroplasia have one of two point mutations in this gene resulting in the same amino acid substitution. This mutation is Gly380Arg, which is a single amino acid substitution in the transmembrane domain of the receptor. (1-4) One hundred percent of people with the Gly380Arg mutation have achondroplasia, thus a causal relationship between genotype and phenotype exists.(3) The FGFR3 receptor is a tyrosine kinase receptor that is found in articular chondrocytes.(2) The receptor is composed of an extracellular domain with three immunoglobulin-like motifs, a transmembrane domain and an intracellular split tyrosine kinase domain. (6) The ligands, fibroblast growth factor (FGF) and heparin, bind to the extracellular domains stabilising the receptor dimer and causing a conformational change in the extracellular domain. This causes cross phosphorylation of the two receptors which triggers a signalling cascade in the cell resulting in the inhibition of bone development by mediating pro-differentiation signals in chondrocytes. (1,3,6) Figure 1 - FGFR3 signalling pathways (From reference 3)
In achondroplasia, the Gly380Arg (and much less commonly found Gly375Cys) mutation in the FGFR3 receptor results in a gain in the FGFR3 receptor function. There is currently no consensus for the exact mechanisms underlying the pathology, but it is thought that the increased FGFR3 activity is due to an increased probability for phosphorylation of the un-ligated mutant dimers due to a change in structure of the un-ligated dimer. (6) Another possibility is that the mutation increases the ligand-independent activation of the FGFR3 receptor. (6) Down regulation of the mutant receptor degradation could also be responsible for an increase in FGFR3 function as this would allow the accumulation of more receptors at the cell surface thus a greater signal could be generated. (6)

In conclusion, the increase in FGFR3 activity is responsible for the pathological features such as short stature and limbs observed in achondroplasia.
The increase in signalling from the FGFR3, expressed in articular chondrocytes, (2) means that the normal function of FGFR3 of inhibiting proliferation and terminal differentiation of growth plate chondrocytes is increased. (1) This results in greater inhibition of linear bone growth by shortening the proliferative phase. (1,6)

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References:
(1) Horton W, Hall J, Hecht J. Achondroplasia. Lancet. 2007;370(9582):162-172.
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(4) Wright M, Irving M. Clinical management of achondroplasia. Archives of Disease in Childhood. 2011;97(2):129-134.
(5) He L, Serrano C, Niphadkar N, Shobnam N, Hristova K. Effect of the G375C and G346E Achondroplasia Mutations on FGFR3 Activation. PLoS ONE. 2012;7(4):e34808.
(6) He L, Horton W, Hristova K. Physical Basis behind Achondroplasia, the Most Common Form of Human Dwarfism. Journal of Biological Chemistry. 2010;285(39):30103-30114.
(7) Ireland P, Pacey V, Zankl A, Edwards P, Johnson L, Savarirayan R. Optimal management of complications associated with achondroplasia. TACG.
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