FGFR1 – Jackson-Weiss syndrome

Heterozygous gain-of-function variants in FGFR1 have been implicated in Jackson-Weiss syndrome, an autosomal dominant craniosynostosis and foot malformation disorder. A patient presenting with brachydactyly and broad halluces was found to carry an activating c.755C>G (p.Pro252Arg) substitution in the IgII–III linker of FGFR1, recapitulating molecular changes seen in other FGFR-related craniosynostoses (PMID:10861678). No additional unrelated cases or familial segregation have been reported to date.

Functional characterization of the Pro252Arg mutant receptor demonstrated enhanced affinity for FGF ligands and formation of additional receptor–ligand hydrogen bonds, as shown by surface plasmon resonance and X-ray crystallography. These mechanistic data, analogous to those reported for Pro→Arg mutations in FGFR2 and FGFR3, support a gain-of-function pathogenic mechanism in Jackson-Weiss syndrome (PMID:14613973).

References

• American journal of medical genetics • 2000 • Clinical findings in a patient with FGFR1 P252R mutation and comparison with the literature PMID:10861678
• Human molecular genetics • 2004 • Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity PMID:14613973

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