Mutations in the third immunoglobulin domain of the fibroblast growth factor receptor-2 gene in Crouzon syndrome

Abstract

Craniosynostosis, which affects approximately 1 in 2000 children, is the result of the abnormal development and/or premature fusion of the cranial sutures. Studies of mutations in patients with craniosynostosis have shown that the family of fibroblast growth factor receptor genes are extremely important in the correct formation of the skull, and digits. Mutations in the third immunoglobulin domain of fibroblast growth factor receptor 2 (FGFR2), in part of the molecule corresponding to a tissue specific isoform (IIIc), can cause both Crouzon and Pfeiffer syndromes. Two specific mutations in the linking region between the second and third immunoglobulin domains of FGFR2 occur in Apert syndrome. We present here mutations associated with the Crouzon syndrome, also in the third immunoglobulin domain but in an upstream exon. This exon is expressed in both tissue isoforms. Five different mutations were detected in 11 unrelated individuals. A cysteine to phenylalanine change was found in six individuals. This cysteine forms half of the disulphide bridge maintaining the secondary structure of the immunoglobulin domain. The first deletion within an FGFR gene is reported. Together with mutations in exon IIIc these account for 25 mutations out of 40 Crouzon patients studied in our combined series (5).

Mutation analysis of Crouzon syndrome in Taiwanese patients

“…The Tyr281Cys illustrates a gain of a cysteine residue located just three amino acids away from Cys278. Another mutation, A-C transversion at nucleotide 866, was found to cause a Gln289Pro substitution, which was previously detected by Oldridge et al (12).…”

Clinical variability in patients with Apert's syndrome

“…The compilation of our results and those of previous molecular studies [7,8,11,13,18] is presented in Table 2. Of 203 patients, the proportion of the two types of mutation is 65% S252W/34% P253R.…”

“…The small number of mutated codons is in sharp contrast with the multiple mutation sites of FGFR2 seen in other craniosynostosis syndromes such as Crouzon's, Pfeiffer, and Jackson-Weiss. [6,7,9,11] This specificity of mutation sites and the high mutation rate can be compared with the mutation of FGFR3 seen in achondroplasia. [2,15,16] A fetus with Apert's syndrome had a double nucleotide substitution that predicted a serine substitution.…”

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.…”