Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome

Wilkie, Andrew O.M.; Slaney, Sarah F.; Oldridge, Michael; Poole, Michael D.; Ashworth, Geraldine J.; Hockley, A. D.; Hayward, Richard; David, David J.; Pulleyn, Louise J.; Rutland, Paul; Malcolm, S; Winter, R M; Reardon, William

doi:10.1038/ng0295-165

Cited by 846 publications

(509 citation statements)

References 66 publications

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“…65 The frequency of new mutations, responsible for craniosynostosis syndromes is estimated as 1 : 65 000 live births. Most Apert syndrome cases result from one of two site (C755G and C758G) mutations in the fibroblast FGFR2 occurring in a normal father's germ line.…”

Section: Autosomal Dominant (Ad) Diseasesmentioning

confidence: 99%

Advanced paternal age and reproductive outcome

Wiener-Megnazi¹,

Auslender²,

Dirnfeld³

2011

Asian J Androl

102

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Women have been increasingly delaying the start of motherhood in recent decades. The same trend is seen also for men. The influence of maternal age on fertility, chromosomal anomalies, pregnancy complications, and impaired perinatal and post-natal outcome of offspring, has been thoroughly investigated, and these aspects are clinically applied during fertility and pregestational counseling. Male aging and reproductive outcome has gained relatively less attention. The purpose of this review is to evaluate updated and relevant literature on the effect of paternal age on reproductive outcome.

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Section: Autosomal Dominant (Ad) Diseasesmentioning

confidence: 99%

Advanced paternal age and reproductive outcome

Wiener-Megnazi¹,

Auslender²,

Dirnfeld³

2011

Asian J Androl

102

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“…6). Up-regulation of Erk1/2 protein also provided increased substrate for signaling by means of Fgfr, a known pathway for inducing premature suture closure (Muenke et al, 1994;Wilkie et al, 1995;Bellus et al, 1996;Kim et al, 2003). This increase in Erk1/2 protein expression was demonstrated in calvarial tissues pretreated with Tgf-␤2, and these tissues had greater and more sustained Erk1/2 phosphorylation in response to Fgf2 than tissues not treated with Tgf-␤2.…”

Section: Discussionmentioning

confidence: 96%

“…The first identified mutations were in genes for transcription factors MSX2 and TWIST (Jabs et al, 1993(Jabs et al, , 1994Liu et al, 1994Liu et al, , 1995el Ghouzzi et al, 1997;Howard et al, 1997). Mutations in genes for fibroblast growth factor receptor (FGFR) and transforming growth factor ␤ (TGF-␤) receptor II (T␤R-II) have also been associated with craniosynostotic disorders (Muenke et al, 1994;Wilkie et al, 1995;Bellus et al, 1996;Loeys et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Erk1/2 signaling is required for Tgf‐β2–induced suture closure

Opperman

Fernandez

et al. 2005

Developmental Dynamics

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Transforming growth factors ␤ (Tgf-␤s) act by means of Smad signaling pathways and may also interact with the mitogen-activated protein kinase pathway. The hypothesis was tested that Erk1/2 signaling is required for Tgf-␤2-induced suture closure, by culturing embryonic mouse calvariae in the presence of Tgf-␤2 with or without Erk1/2 inhibitor PD98059 (PD). Suture widths were measured daily, and microdissected sutures and bones were homogenized and protein analyzed by Western blots. Tgf-␤2 induced narrowing of the sutures after 72 hr, an effect inhibited by treatment with PD. Erk1/2 and Egf but not Smad2/3 protein expression was up-regulated by Tgf-␤2 calvarial tissues at 72 hr. PD inhibited endogenous and Tgf-␤2-stimulated Erk1/2 protein as well as Tgf-␤2-stimulated Egf, but increased Smad2/3 protein expression. In tissues harvested 0, 15, and 30 min after exposure to Tgf-␤2, Erk1/2 phosphorylation was up-regulated after 15 min, an effect abrogated by the simultaneous addition of PD. In summary, Tgf-␤2 stimulated Erk1/2 phosphorylation and induced Egf and Erk1/2 expression, associated with suture closure after 72 hr. Blocking Erk1/2 activity with PD inhibited these effects but increased Smad2/3 expression. We postulate that Tgf-␤2 regulates suture closure directly by means of phosphorylation of Erk1/2 and indirectly by up-regulating Erk1/2, a substrate for Fgf receptor signaling required for Fgf induction of premature suture obliteration.

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“…Recent studies have demonstrated that mutations in three of the four known FGFR genes are responsible for a variety of craniosynostosis syndromes, including Crouzon (4-6), Apert (7,8), Pfeiffer (9,10), and Jackson-Weiss (3,9,11) syndromes. Crouzon syndrome shows a broader spectrum of mutations in the FGFR2 gene, and occasionally patients with Crouzon syndrome share identical mutations (Cys278Phe, Cys342Arg, and Cys342Tyr) with patients with Pfeiffer and Jackson-Weiss syndromes, respectively (3,8,10,11). The majority of mutations in FGFR2 are missense substitutions clustered around the third extracellular immunoglobulin-like domain, encoded by exons IIIa and IIIc.…”

Section: Introductionmentioning

confidence: 99%

Mutation analysis of Crouzon syndrome in Taiwanese patients

Chang

Wan

Tsai

et al. 2006

Clinical Laboratory Analysis

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Crouzon syndrome is an autosomal-dominant disorder that causes premature fusion of the cranial suture. Crouzon, Pfeiffer, and Apert syndromes are caused by mutations in the extracellular, third immunoglobulinlike domain, and adjacent linker regions (exons IIIa and IIIc) of the fibroblast growth factor receptor 2 (FGFR2) gene. We screened 12 Crouzon syndrome patients for mutations in exons IIIa and IIIc of the FGFR2 gene by polymerase chain reaction (PCR) and direct sequencing. Mutations were detected in nine of 12 patients at amino acid positions 278 , 281, 289, 342, and 354. More than half of the studied Crouzon patients carried a mutation resulting in either the loss or gain of a cysteine residue. A novel missense Ser354Phe substitution at exon IIIc of the human FGFR2 gene was found. According to our results, sequencing analysis of IgIII domain of the FGFR2 gene can lead to a genetic diagnosis of Crouzon syndrome.

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Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome

Cited by 846 publications

References 66 publications

Advanced paternal age and reproductive outcome

Advanced paternal age and reproductive outcome

Erk1/2 signaling is required for Tgf‐β2–induced suture closure

Mutation analysis of Crouzon syndrome in Taiwanese patients

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