A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome

Muenke, Maximilian; Schell, Ute; Hehr, Andreas; Robin, Nathaniel H.; Losken, H. Wolfgang; Schinzel, Albert; Pulleyn, Louise J.; Rutland, Paul; Reardon, William; Malcolm, Sue

doi:10.1038/ng1194-269

Cited by 590 publications

(313 citation statements)

References 26 publications

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“…Polymerase chain reaction amplification of the TWIST gene was performed using conditions and primers specific for the TWIST gene [Howard et al, 1997]. Using techniques described previously [Muenke et al, 1994], exon 5 of the FGFR 1 gene was amplified and analysis was performed to detect the C to G mutation that results in the Pro252Arg amino acid substitution. Exons 8 and 10 of the FGFR 2 gene were amplified using primers and conditions described by [Meyers et al, 1996].…”

Section: Genetic Analysis Mutational Analysis For Jag1mentioning

confidence: 99%

Craniosynostosis in Alagille syndrome

et al. 2002

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Alagille syndrome is a multisystem developmental disorder with primary involvement of the liver, heart, skeleton, eyes and facial structures, and demonstrates highly variable expressivity with respect to all of the involved systems. Alagille syndrome is caused by mutations in the Jagged1 gene. Jagged1 is a ligand in the Notch signaling pathway that has been shown to regulate early cell fate determination. Mutations in Jagged1 have been identified in approximately 80% of patients with Alagille syndrome. We have recently identified two patients with mutation proven Alagille syndrome who also had unilateral coronal craniosynostosis. Both individuals were screened for mutations in fibroblast growth factor receptor 1, 2, 3 and TWIST genes, all associated with various types of craniosynostosis and no mutations were identified. The finding of a conserved form of craniosynostosis in two unrelated patients with Alagille syndrome and mutations in Jagged1 may indicate that Jagged1 plays a role in cranial suture formation. © 2002 Wiley‐Liss, Inc.

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Section: Genetic Analysis Mutational Analysis For Jag1mentioning

confidence: 99%

Craniosynostosis in Alagille syndrome

et al. 2002

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“…Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males. dominant gain-of-function mutation of FGFR1 underlies a form of craniosynostosis 6 . This mutation is believed to result in enhanced affinity for certain FGF ligands 7 .…”

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confidence: 99%

Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome

et al. 2003

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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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A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome

Cited by 590 publications

References 26 publications

Craniosynostosis in Alagille syndrome

Craniosynostosis in Alagille syndrome

Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome

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

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