title: Characterization of the first FGFRL1 mutation identified in a craniosynostosis patient.
abstract: Fibroblast growth factor receptor-like 1 (FGFRL1) is a recently discovered transmembrane protein whose functions remain unclear. Since mutations in the related receptors FGFR1-3 cause skeletal malformations, DNA samples from 55 patients suffering from congenital skeletal malformations and 109 controls were searched for mutations in FGFRL1. One patient was identified harboring a frameshift mutation in the intracellular domain of this novel receptor. The patient showed craniosynostosis, radio-ulnar synostosis and genital abnormalities and had previously been diagnosed with Antley-Bixler syndrome. The effect of the FGFRL1 mutation was studied in vitro. In a reporter gene assay, the wild-type as well as the mutant receptor inhibited FGF signaling. However, the mutant protein differed from the wild-type protein in its subcellular localization. Mutant FGFRL1 was mainly found at the plasma membrane where it interacted with FGF ligands, while the wild-type protein was preferentially located in vesicular structures and the Golgi complex. Two motifs from the intracellular domain of FGFRL1 appeared to be responsible for this differential distribution, a tandem tyrosine based motif and a histidine-rich sequence. Deletion of either one led to the preferential redistribution of FGFRL1 to the plasma membrane. It is therefore likely that mutant FGFRL1 contributes to the skeletal malformations of the patient.
authors.affiliation: Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Rieckmann
authors.forename: Lei
authors.initials: L
authors.lastname: Zhuang
authors.forename: Christa E
authors.initials: CE
authors.lastname: Flück
authors.forename: Beat
authors.initials: B
authors.lastname: Trueb
mesh_terms: D000818:Animals; D001483:Base Sequence; D015415:Biomarkers; D002460:Cell Line; D002462:Cell Membrane; D003398:Craniosynostoses / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D004705:Endocytosis; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D051500:Receptor, Fibroblast Growth Factor, Type 5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; C417531:FGFRL1 protein, human; D051500:Receptor, Fibroblast Growth Factor, Type 5; D005346:Fibroblast Growth Factors