Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability

Abstract

Mutations have been reported for several craniosynostotic disorders in exon IIIa (exon U or 7) or IIIc (exon B or 9) of the fibroblast growth factor receptor 2 gene (FGFR2). Among the conditions with FGFR2 mutations are two autosomal dominant syndromes, Crouzon and Jackson-Weiss. In this study, 24 Crouzon and one Jackson-Weiss syndrome patients were screened for mutations in the two exons by direct sequencing, and mutations were detected in 28% (7/25) of all cases. Five different mutations were found including two novel (W290G, C342W) and two previously reported, recurrent mutations for Crouzon syndrome (A344A, S354C), and one new mutation for Jackson-Weiss syndrome (C342R). The W290G mutation was found in exon IIIa which is common to both alternatively spliced forms of FGFR2, BEK (expressed predominantly in primordial bones) and KGFR (expressed preferentially in epithelia). Atypical Crouzon syndrome features of epithelial-derived anal and/or external ear anomalies were present in the two affected family members with the mutation. This phenotype possibly reflects the expression of both mutant BEK and KGFR. In addition, the Jackson-Weiss syndrome mutation, C342R, in exon IIIc was observed previously in other craniosynostotic syndromes, Crouzon and Pfeiffer. These results underscore the allelic heterogeneity of these conditions and the complexity of the phenotypic consequences of FGFR2 mutations.

Amino acid properties may be useful in predicting clinical outcome in patients with Kir6.2 neonatal diabetes

“…These results highlight the potential utility of an amino acid scoring system for predicting both diabetic and neurological phenotype by direct comparisons of Grantham scores for novel non-synonymous KCNJ11 mutations affecting previously mutated residues. Further studies investigating its use in predicting other aspects of phenotype, for example treatment response, or its use in other monogenic diseases, such as ABCC8 neonatal diabetes or Crouzon syndrome (13,24,25), where different mutations at the same residues cause variable phenotypes, are warranted.…”

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.…”

“…However, the majority of craniosynostosis syndromes are associated with mutations in Fgfr2 ( Fig. 2; Muenke and Schell 1995;Park et al 1995;Malcolm and Reardon 1996;Webster and Donoghue 1997;Wilkie 1997;Burke et al 1998;Lajeunie et al 1999;Ornitz 2001). The pathophysiology and genetics of craniosynostosis syndromes have been recently reviewed (Wilkie 1997(Wilkie , 2000Cohen 2000b;Britto et al 2001a;Wilkie and Morriss-Kay 2001).…”

FGF signaling in the developing endochondral skeleton

“…These disorders have in common craniosynostosis (premature fusion of the cranial sutures) and variably other phenotypes that affect the appendicular skeleton and other organ systems. The craniosynostosis syndromes involving Fgfr2 include Apert syndrome (AS) [18], Beare-Stevenson cutis gyrata [19], Crouzon syndrome (CS) [20][21][22][23][24][25][26][27][28][29][30][31][32], Pfeiffer syndrome (PS) [33][34][35][36][37]23,28,29], Jackson-Weiss syndrome (JWS) [22,23,26] and a non-syndromic craniosynostosis (NSC) [38]. Recently a family has been described with a double mutation in Fgfr2 (S2521, A315S) that is associated with syndactyly but not craniosynostosis [39].…”