Clinical variability in patients with Apert's syndrome

Lajeunie, E; Cameron, Rhoda; Ghouzzi, Vincent El; Parseval, Nathalie de; Journeau, Pierre; Gonzalès, Marie; Delezoïde, Anne Lise; Bonaventure, Jacky; Merrer, Martine Le; Rénier, Dominique

doi:10.3171/jns.1999.90.3.0443

Cited by 113 publications

(93 citation statements)

References 14 publications

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“…(v) In sperm from a healthy 37-year-old donor, we found a double-mutation 755 756CGϾTC (encoding Ser252Phe) present at Ϸ1 in 175,000. A similar heterozygous doublemutation 755 756CGϾTT, also encoding Ser252Phe (Table 1), was previously reported in two children with Apert syndrome (26,28).…”

mentioning

confidence: 74%

Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia

Goriely

McVean²,

Pelt³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

133

109

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Despite the importance of mutation in genetics, there are virtually no experimental data on the occurrence of specific nucleotide substitutions in human gametes. C>G transversions at position 755 of FGF receptor 2 (FGFR2) cause Apert syndrome; this mutation, encoding the gain-of-function substitution Ser252Trp, occurs with a birth rate elevated 200-to 800-fold above background and originates exclusively from the unaffected father. We previously demonstrated high levels of both 755C>G and 755C>T FGFR2 mutations in human sperm and proposed that these particular mutations are enriched because the encoded proteins confer a selective advantage to spermatogonial cells. Here, we examine three corollaries of this hypothesis. First, we show that mutation levels at the adjacent FGFR2 nucleotides 752-754 are low, excluding any general increase in local mutation rate. Second, we present three instances of double-nucleotide changes involving 755C, expected to be extremely rare as chance events. Two of these double-nucleotide substitutions are shown, either by assessment of the pedigree or by direct analysis of sperm, to have arisen in sequential steps; the third (encoding Ser252Tyr) was predicted from structural considerations. Finally, we demonstrate that both major alternative spliceforms of FGFR2 (Fgfr2b and Fgfr2c) are expressed in rat spermatogonial stem cell lines. Taken together, these observations show that specific FGFR2 mutations attain high levels in sperm because they encode proteins with gain-of-function properties, favoring clonal expansion of mutant spermatogonial cells. Among FGFR2 mutations, those causing Apert syndrome may be especially prevalent because they enhance signaling by FGF ligands specific for each of the major expressed isoforms.Apert syndrome ͉ FGF receptor 2 ͉ paternal age ͉ selfish mutation

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mentioning

confidence: 74%

Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia

Goriely

McVean²,

Pelt³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

133

109

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“…To date, only four other FGFR2 mutations in five patients have been reported. [22][23][24][25][26] The entire coding region of FGFR2, and deletions or Alu events in FGFR2 have been excluded.…”

Section: Discussionmentioning

confidence: 99%

Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants

et al. 2014

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Craniosynostosis, caused by the premature fusion of one or more of the cranial sutures, can be classified into non-syndromic or syndromic and by which sutures are affected. Clinical assignment is a difficult challenge due to the high phenotypic variability observed between syndromes. During routine diagnostics, we screened 182 Spanish craniosynostosis probands, implementing a four-tiered cascade screening of FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1. A total of 43 variants, eight novel, were identified in 113 (62%) patients: 104 (92%) detected in level 1; eight (7%) in level 2 and one (1%) in level 3. We subsequently screened additional genes in the probands with no detected mutation: one duplication of the IHH regulatory region was identified in a patient with craniosynostosis Philadelphia type and five variants, four novel, were identified in the recently described TCF12, in probands with coronal or multisuture affectation. In the 19 Saethre-Chotzen syndrome (SCS) individuals in whom a variant was detected, 15 (79%) carried a TWIST1 variant, whereas four (21%) had a TCF12 variant. Thus, we propose that TCF12 screening should be included for TWIST1 negative SCS patients and in patients where the coronal suture is affected. In summary, a molecular diagnosis was obtained in a total of 119/182 patients (65%), allowing the correct craniosynostosis syndrome classification, aiding genetic counselling and in some cases provided a better planning on how and when surgical intervention should take place and, subsequently the appropriate clinical follow up.

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“…The presence of these additional interactions will likely strengthen FGF2-FGFR2 affinity and is consistent with data demonstrating that, compared to wild-type FGFR2, the Ser252Trp mutant has an approximate 6.5-fold decrease in the rate of dissociation (k off ) from FGF2 (13). Of interest, there are two instances of AS patients with a Ser252Phe mutation (6,8) that is likely to activate FGFR2 through a similar mechanism.…”

Section: Fgf2 In Complex With Ser252trp Mutant Fgfr2mentioning

confidence: 99%

“…Numerous other anomalies, including central nervous system abnormalities, cardiovascular defects, urogenital anomalies, and dermatologic manifestations, also have been observed in AS patients. Interestingly, statistically significant differences were described for severity of syndactyly and presence of cleft palate between two subgroups of AS patients with Ser-252 3 Trp (Ser252Trp) or Pro-253 3 Arg (Pro253Arg) mutations (5,6), which account for Ϸ67% and 32% of AS patients (6)(7)(8)(9), respectively.…”

mentioning

confidence: 99%

Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome

Ibrahimi

Eliseenkova

Plotnikov

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

183

138

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Apert syndrome (AS) is characterized by craniosynostosis (premature fusion of cranial sutures) and severe syndactyly of the hands and feet. Two activating mutations, Ser-252 3 Trp and Pro-253 3 Arg, in fibroblast growth factor receptor 2 (FGFR2) account for nearly all known cases of AS. To elucidate the mechanism by which these substitutions cause AS, we determined the crystal structures of these two FGFR2 mutants in complex with fibroblast growth factor 2 (FGF2) . These structures demonstrate that both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity. Moreover, based on these structures and sequence alignment of the FGF family, we propose that the Pro-253 3 Arg mutation will indiscriminately increase the affinity of FGFR2 toward any FGF. In contrast, the Ser-252 3 Trp mutation will selectively enhance the affinity of FGFR2 toward a limited subset of FGFs. These predictions are consistent with previous biochemical data describing the effects of AS mutations on FGF binding. Alterations in FGFR2 ligand affinity and specificity may allow inappropriate autocrine or paracrine activation of FGFR2. Furthermore, the distinct gain-of-function interactions observed in each crystal structure provide a model to explain the phenotypic variability among AS patients.T he fibroblast growth factor receptor (FGFR) signaling pathway is involved in a variety of critical physiological and pathological processes (1). Activating mutations in the extracellular domains of FGFR1-3 are responsible for many human skeletal disorders (2), including the craniosynostosis syndromes (3). The craniosynostosis syndromes are mostly caused by gainof-function mutations in FGFR2 and include Apert syndrome (AS), Crouzon syndrome, Crouzon syndrome with acanthosis nigricans, coronal craniosynostosis, Pfeiffer syndrome, JacksonWeiss syndrome, Antley-Bixler syndrome, and Beare-Stevenson cutis gyrata. AS [ref. 4; Online Mendelian Inheritance in Man database at http:͞͞www3.ncbi.nlm.nih.gov͞omim͞], the most severe of the craniosynostosis syndromes, is unique among the craniosynostosis syndromes in that it is also characterized by severe syndactyly (bony and cutaneous) of the hands and feet. Numerous other anomalies, including central nervous system abnormalities, cardiovascular defects, urogenital anomalies, and dermatologic manifestations, also have been observed in AS patients. Interestingly, statistically significant differences were described for severity of syndactyly and presence of cleft palate between two subgroups of AS patients with Ser-252 3 Trp (Ser252Trp) or Pro-253 3 Arg (Pro253Arg) mutations (5, 6), which account for Ϸ67% and 32% of AS patients (6-9), respectively.Most mutations in the extracellular domain of FGFR2 cause receptor activation by facilitating dimerization. For example, Crouzon syndrome is caused by mutations that create an unpaired cysteine residue either by gain or loss of an ectodomain cysteine residue or by destabilizing disulfide bond formation in Ig-like domain 3 (D3)....

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Clinical variability in patients with Apert's syndrome

Cited by 113 publications

References 14 publications

Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia

Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia

Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants

Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome

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