Analysis of the mutational spectrum of the FGFR2 gene in Pfeiffer syndrome

Cornejo-Roldan, Laura R.; Roessler, Erich; Muenke, Maximilian

doi:10.1007/s004390050979

Cited by 68 publications

(50 citation statements)

References 32 publications

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“…On the basis of previous studies 15,20 and our own experience, the mutation detection rate appears to depend largely on the accuracy of the original diagnosis and the sensitivity of the detection method. In our study, all patients were examined by the same physicians and complete clinical and radiological data were recorded, so that the criteria for phenotypic classification were highly homogeneous allowing recognition of the Crouzonoid facies.…”

Section: Discussionmentioning

confidence: 91%

“…27 Tyrosine 340 when converted into histidine gave rise to CS in 8/8 patients (Table 4). By contrast conversion into cysteine reproducibly led to very severe forms of PS 15,20,28 with cloverleaf skull, severe ocular proptosis, hydrocephalus, and early demise in some cases (Table 3). Mutations eliminating cysteine 342 were also noticeable with respect to phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome

et al. 2006

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Crouzon Syndrome (CS), Pfeiffer syndrome (PS) and the phenotypically related Jackson-Weiss (JW) variant are three craniosynostotic conditions caused by heterozygous mutations in Fibroblast Growth Factor Receptor (FGFR) genes. Screening a large cohort of 84 patients with clinical features of CS, PS or JW by direct sequencing of genomic DNA, enabled FGFR1, 2 or 3 mutation detection in 79 cases. Mutations preferentially occurred in exons 8 and 10 of FGFR2 encoding the third Ig loop of the receptor. Among the 74 FGFR2 mutations that we identified, four were novel including three missense substitutions causing CS and a 2 bp deletion creating a premature stop codon and producing JW phenotype. Five FGFR2 mutations were found in one of the two tyrosine kinase subdomains and one in the Ig I loop. Interestingly, two FGFR2 mutations creating cysteine residues (W290C and Y340C) caused severe forms of PS while conversion of the same residues into another amino-acid (W290G/R, Y340H) resulted in Crouzon phenotype exclusively. Our data provide conclusive evidence that the mutational spectrum of FGFR2 mutations in CS and PS is wider than originally thought. Genotype-phenotype analyses based on our cohort and previous studies further indicate that in spite of some overlap, PS and CS are preferentially accounted for by two distinct sets of FGFR2 mutations. A limited number of recurrent amino-acid changes (W290C, Y340C, C342R and S351C) is commonly associated with the most severe Pfeiffer phenotypes of poor prognosis.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome

et al. 2006

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“…The closest mutation downstream of Ala315Ser described to date is the substitution Asp321Ala, located in a short α-helical (D) segment [34][35][36] and identified in four cases of Pfeiffer syndrome. 22,27,37 No experimental studies have directly addressed the pathologic mechanism of this mutation, but disruption of the immunoglobulin fold leading to covalent dimerisation and constitutive activation of FGFR2 is the mechanism by which other mutations of the IgIIIc domain are believed to act. 38 Several lines of evidence argue against the Ala315Ser mutation having a similarly gross disruptive effect.…”

Section: Discussionmentioning

confidence: 99%

“…20,[22][23][24][25][26][27][28][29] These mutations are predicted to affect correct recognition of the IgIIIc acceptor splice site, and in three cases, alternative use of the IgIIIb exon has been demonstrated. 20 Several G ® T transversions, all associated with Pfeiffer syndrome, have been described in the first nucleotide of the IgIIIc exon.…”

Section: Discussionmentioning

confidence: 99%

A novel mutation, Ala315Ser, in FGFR2: a gene–environment interaction leading to craniosynostosis?

et al. 2000

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Mutations in the fibroblast growth factor receptor 1, 2 and 3 (FGFR1, -2 and -3) and TWIST genes have been identified in several syndromic forms of craniosynostosis. There remains, however, a significant number of patients with non-syndromic craniosynostosis in whom no genetic cause can be identified. We describe a novel heterozygous mutation of FGFR2 (943G ® T, encoding the amino acid substitution Ala315Ser) in a girl with non-syndromic unicoronal craniosynostosis. The mutation is also present in her mother and her maternal grandfather who have mild facial asymmetry but do not have craniosynostosis. None of these individuals has the Crouzonoid appearance typically associated with FGFR2 mutations. However, the obstetric history revealed that the proband was in persistent breech presentation in utero and was delivered by Caesarean section, at which time compression of the skull was apparent. We propose that this particular FGFR2 mutation only confers a predisposition to craniosynostosis and that an additional environmental insult (in this case foetal head constraint associated with breech position) is necessary for craniosynostosis to occur. To our knowledge, this is the first report of an interaction between a weakly pathogenic mutation and intrauterine constraint, leading to craniosynostosis.

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“…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].…”

Section: Human Skeletal Disease Syndromes: the Fgf Connectionmentioning

confidence: 99%

FGF signaling in the developing endochondral skeleton

Ornitz¹

2005

Cytokine & Growth Factor Reviews

324

259

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Mutations in fibroblast growth factor receptors (Fgfrs) are the etiology of many craniosynostosis and chondrodysplasia syndromes in humans. The phenotypes associated with these human syndromes and the phenotypes resulting from targeted mutagenesis in the mouse have defined essential roles for FGF signaling in both endochondral and intramembranous bone development. In this review, I will focus on the role of FGF signaling in chondrocytes and osteoblasts and how FGFs regulate the growth and development of endochondral bone. KeywordsFGF; Skeletal development; Craniosynostosis; Achondroplasia; Receptor tyrosine kinase Human skeletal disease syndromes: the FGF connectionFgfrs were known to be expressed in the developing skeleton. However, a functional link between FGF signaling and skeletal development was not appreciated until the discovery that achondroplasia (ACH), the most common form of skeletal dwarfism in humans, was caused by a missense mutation in Fgfr3 [1][2][3][4][5]. Following this initial discovery, a milder form of dwarfism, hypochondroplasia (HCH) [6,7], and a more severe form of dwarfism, thanatophoric dysplasia (TD) [3,[8][9][10], were also found to result from mutations in Fgfr3.In addition to the chondrodysplasia syndromes, many other human skeletal dysplasias have been attributed to mutations in Fgfrs 1, 2 and 3 [11][12][13][14][15][16][17]. 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]. However, individually, these mutations are associated with low-penetrance craniosynostosis.In addition to the single mutation in Fgfr1 (P252R) that causes Pfeiffer syndrome [40][41][42]29], a rare mutation has been identified that causes osteoglophonic dysplasia (OD), a disease characterized by craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge, as well as the rhizomelic dwarfism and nonossifying bone lesions [43]. One patient has also been described with Jackson-Weiss syndrome and a P252R mutation in Fgfr1 Recently, a mutation in Fgfr3 (P250R) has been described that causes Muenke syndrome (MS), which is characterized by craniosynostosis and variably other skeletal and neurological phenotypes [38,46,47]. Another mutation in Fgfr3 (A391E) causes Crouzon syndrome with acanthosis nigricans, now referred to as crouzonodermoskeletal syndrome [48][49][50][51][52]24].All of the skeletal disease syndromes are caused by autosomal dominant mutations and frequently arise sporadically...

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Analysis of the mutational spectrum of the FGFR2 gene in Pfeiffer syndrome

Cited by 68 publications

References 32 publications

Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome

Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome

A novel mutation, Ala315Ser, in FGFR2: a gene–environment interaction leading to craniosynostosis?

FGF signaling in the developing endochondral skeleton

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