Why Crouzon Syndrome occurs

There are many versions of the FGFR2 gene that are associated with Crouzon Syndrome. One example which will be explored on this page is the replacement of a piece of code in exon 9, illustrated in Figure 6. Note that exon 9 is part of the Ig III region of the protein. The letter G in the DNA sequence of the gene at position 1204 is replaced with an A, resulting in a change in the primary structure of the protein, which then goes on to affect the secondary and tertiary structures, and ultimately the activation of the protein that leads to cell signalling. [1,2]

Figure 6. A comparison of the typical DNA sequence found in exon 9 of the FGFR2 gene, compared with an altered version. The cysteine at position 342 is turned into another amino acid called tyrosine.

normal

altered

Figure 7. Structural change to the FGFR2 protein due to altered DNA sequence. In the normal version of the protein, a bridge can be formed between CYS-342 and CYS-278 shown in yellow (left). The replacement of cysteine with tyrosine means the bridge cannot be formed, and the structure is altered (right). Images created with data from https://www.rcsb.org/structure/1E0O using The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC.

Result: Crouzon SYNDROME

The replacement of cysteine at position 342 means the now unpaired cysteine at position 278 is free to form bridges with another free cysteine in a different FGFR2 protein. This linkage of the two proteins allows the receptor to be activated without the presence of any FGF, leading to excessive signalling inside the cell and stimulating unwanted cell growth. [1,2]

Bone cells mature too early, and parts of the skull end up fusing together faster than usual, resulting in the characteristic misshapen head seen in many with Crouzon Syndrome. Other abnormal growth promotion in skin and blood cells result in non-typical eye positioning, jaw displacement, and hearing loss.

Other alterations to the gene have a similar effect on the sulfide bridges in the protein structure, hence not everyone with Crouzon Syndrome will have the same change in their DNA. [3,4]

References

  1. Robertson SC, Meyer AN, Hart KC, Galvin BD, Webster MK, Donoghue DJ. Activating mutations in the extracellular domain of the fibroblast growth factor receptor 2 function by disruption of the disulfide bond in the third immunoglobulin-like domain. Proc Natl Acad Sci U S A. 1998 [cited 2022 Oct 21] 95(8):4567-72. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC22530/

  2. Neilson KM, Friesel RE, 1995. Constitutive Activation of Fibroblast Growth Factor Receptor-2 by a Point Mutation Associated with Crouzon Syndrome. J. Biol. Chem 1997 [cited 2022 Oct 21] 270 (44), 26037–26040. Available from: https://pubmed.ncbi.nlm.nih.gov/7592798/

  3. Reardon W, Winter RM, Rutland P. Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet. 1994 [cited 2022 Oct 21] 8:98–103. Available from: https://www.nature.com/articles/ng0994-98

  4. Kan SH, Elanko N, Johnson D, Cornejo-Roldan L, Cook J, Reich EW, Tomkins S, Verloes A, Twigg SR, Rannan-Eliya S, McDonald-McGinn DM, Zackai EH, Wall SA, Muenke M, Wilkie AO. Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis. Am J Hum Genet. 2002 [cited 2022 Oct 21];70(2):472-86. Available from: https://europepmc.org/article/MED/11781872