Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans

Abstract

Crouzon syndrome, an autosomal dominant condition characterized by craniosynostosis, ocular proptosis and midface hypoplasia, is associated with mutations in fibroblast growth factor receptor 2 (FGFR2) (refs 1-3). For example, we have identified 10 different mutations in the FGFR2 extracellular immunoglobulin III (IgIII) domain in 50% (16/32) of our Crouzon syndrome patients. All mutations described so far for other craniosynostotic syndromes with associated limb anomalies--Jackson-Weiss, Pfeiffer, and Apert--also occur in the extracellular domain of FGFR2, as well as FGFR1 for Pfeiffer syndrome. In contrast, only FGFR3 mutations have been reported in dwarfing conditions--achondroplasia, thanatophoric dysplasia, and hypochondroplasia. For achondroplasia, greater than 99% of mutations occur in the FGFR3 transmembrane domain. We now report the unexpected observation of a FGFR3 transmembrane domain mutation, Ala391Glu, in three unrelated families with Crouzon syndrome and acanthosis nigricans, a specific skin disorder of hyperkeratosis and hyperpigmentation. The association of non-dwarfing and even non-skeletal conditions with FGFR3 mutations reveals the potential for a wide range of FGFR pleiotropic effects as well as locus heterogeneity in Crouzon syndrome. Our study underscores the biologic complexity of the FGFR gene family.

Peptide-based interference of the transmembrane domain of neuropilin-1 inhibits glioma growth in vivo

“…This domain has been ignored so far because of the lack of efficient tools allowing detailed analysis of this hydrophobic environment. Although initially described for glycophorin-A (Lemmon et al, 1992), the function of the transmembrane domain is nowadays a growing field of interest because within this particular domain, the targeted motif has crucial implications in diverse pathological situations as shown by the consequence of various point mutations of the TM domain of c-neu receptor (Bargmann and Weinberg, 1988;Weiner et al, 1989), FGFR3 receptor (Meyers et al, 1995;Webster and Donoghue, 1996;Orian-Rousseau and Ponta, 2008), FGFR2 (Forbes et al, 2002) or RET (Tessitore et al, 1999). In all cases, the effects relate to the GxxxG motif Inhibition of glioma growth using neuroplin-1 peptide C Nasarre et al (or equivalent small amino-acid-xxx-small amino-acid motif) that is supposed to drive the dimerization of the transmembrane domains (Senes et al, 2004).…”

Receptor tyrosine kinase transmembrane domains

“…Often these mutations substitute aliphatic amino acids that participate in the dimer interface with Glu or Asp, which have hydrogen bonding capabilities. One example is the Ala391Glu mutation in FGFR3, which has been identified as a somatic mutation in bladder cancer 36 and as a germ-line mutation in Crouzon syndrome with acanthosis nigricans, 37 an autosomal dominant disorder characterized by the following three phenotypic features: (1) mild disturbances of the growth plate of the long bones, (2) premature ossification of the skull (craniosynostosis) and (3) skin hyperpigmentation and hyperkeratosis. A second example is the Val664Glu mutation in rat Neu which has been shown to be oncogenic.…”

FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease

“…Since this discovery, the etiology of many other human skeletal dysplasias have been attributed to specific mutations in the genes encoding FGF receptors 1, 2, and 3 (Muenke and Schell 1995; Wilkie 1997; Cohen 2000c;Britto et al 2001a;Ornitz 2001). These disorders can be broadly classified into two groups: (1) the dwarfing chondrodysplasia syndromes, which include hypochondroplasia (HCH) (Bellus et al 1995), achondroplasia (ACH) (Rousseau et al 1994;Shiang et al 1994;Ikegawa et al 1995;SupertiFurga et al 1995), thanatophoric dysplasia (TD) (Rousseau et al 1995(Rousseau et al , 1996Tavormina et al 1995a,b); and (2) the craniosynostosis syndromes, which include Apert syndrome (AS) (Wilkie et al 1995b), Beare-Stevenson cutis gyrata , Crouzon syndrome (CS) (Jabs et al 1994;Reardon et al 1994;Gorry et al 1995;Meyers et al 1995Meyers et al , 1996Oldridge et al 1995;Park et al 1995;Rutland et al 1995;Schell et al 1995;Steinberger et al 1995;Wilkie et al 1995a), Pfeiffer syndrome (PS) (Muenke et al 1994;Lajeunie et al 1995;Rutland et al 1995;Schell et al 1995;Meyers et al 1996), JacksonWeiss syndrome (JWS) (Jabs et al 1994;Park et al 1995;Meyers et al 1996), and a non-syndromic craniosynostosis (NSC) (Bellus et al 1996). All of these mutations are autosomal dominant and frequently arise sporadically.…”