A glycine 375-to-cysteine substitution in the transmembrane domain of the fibroblast growth factor receptor-3 in a newborn with achondroplasia

1995 ◽  
Vol 154 (3) ◽  
pp. 215-219 ◽  
Author(s):  
A. Superti-Furga ◽  
G. Eich ◽  
H. U. Bucher ◽  
J. Wisser ◽  
A. Giedion ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Transmembrane Domain ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Cysteine Substitution

scholarly journals The Molecular and Genetic Basis of Fibroblast Growth Factor Receptor 3 Disorders: The Achondroplasia Family of Skeletal Dysplasias, Muenke Craniosynostosis, and Crouzon Syndrome with Acanthosis Nigricans*

2000 ◽  
Vol 21 (1) ◽  
pp. 23-39 ◽  
Author(s):  
Zoltan Vajo ◽  
Clair A. Francomano ◽  
Douglas J. Wilkin
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Acanthosis Nigricans ◽  
Fibroblast Growth Factor Receptor ◽  
Transmembrane Domain ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Paternal Age ◽  
Fibroblast Growth ◽  
Crouzon Syndrome

Abstract Achondroplasia, the most common form of short-limbed dwarfism in humans, occurs between 1 in 15,000 and 40,000 live births. More than 90% of cases are sporadic and there is, on average, an increased paternal age at the time of conception of affected individuals. More then 97% of persons with achondroplasia have a Gly380Arg mutation in the transmembrane domain of the fibroblast growth factor receptor (FGFR) 3 gene. Mutations in the FGFR3 gene also result in hypochondroplasia, the lethal thanatophoric dysplasias, the recently described SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) dysplasia, and two craniosynostosis disorders: Muenke coronal craniosynostosis and Crouzon syndrome with acanthosis nigricans. Recent evidence suggests that the phenotypic differences may be due to specific alleles with varying degrees of ligand-independent activation, allowing the receptor to be constitutively active. Since the Gly380Arg achondroplasia mutation was recognized, similar observations regarding the conserved nature of FGFR mutations and resulting phenotype have been made regarding other skeletal phenotypes, including hypochondroplasia, thanatophoric dysplasia, and Muenke coronal craniosynostosis. These specific genotype-phenotype correlations in the FGFR disorders seem to be unprecedented in the study of human disease. The explanation for this high degree of mutability at specific bases remains an intriguing question.

scholarly journals Identification and characterization of an inhibitory fibroblast growth factor receptor 2 (FGFR2) molecule, up-regulated in an Apert Syndrome mouse model

2011 ◽  
Vol 436 (1) ◽  
pp. 71-81 ◽  
Author(s):  
Lee M. Wheldon ◽  
Naila Khodabukus ◽  
Susannah J. Patey ◽  
Terence G. Smith ◽  
John K. Heath ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mouse Model ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Transmembrane Domain ◽  
Growth Factor Receptor ◽  
Apert Syndrome ◽  
Fibroblast Growth

AS (Apert syndrome) is a congenital disease composed of skeletal, visceral and neural abnormalities, caused by dominant-acting mutations in FGFR2 [FGF (fibroblast growth factor) receptor 2]. Multiple FGFR2 splice variants are generated through alternative splicing, including PTC (premature termination codon)-containing transcripts that are normally eliminated via the NMD (nonsense-mediated decay) pathway. We have discovered that a soluble truncated FGFR2 molecule encoded by a PTC-containing transcript is up-regulated and persists in tissues of an AS mouse model. We have termed this IIIa–TM as it arises from aberrant splicing of FGFR2 exon 7 (IIIa) into exon 10 [TM (transmembrane domain)]. IIIa–TM is glycosylated and can modulate the binding of FGF1 to FGFR2 molecules in BIAcore-binding assays. We also show that IIIa–TM can negatively regulate FGF signalling in vitro and in vivo. AS phenotypes are thought to result from gain-of-FGFR2 signalling, but our findings suggest that IIIa–TM can contribute to these through a loss-of-FGFR2 function mechanism. Moreover, our findings raise the interesting possibility that FGFR2 signalling may be a regulator of the NMD pathway.

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