Multiple congenital malformations of Wolf-Hirschhorn syndrome are recapitulated in Fgfrl1 null mice.
Wolf-Hirschhorn syndrome (WHS) is caused by deletions in the short arm of chromosome 4 (4p) and occurs in about one per 20,000 births. Patients with WHS display a set of highly variable characteristics including craniofacial dysgenesis, mental retardation, speech problems, congenital heart defects, short stature and a variety of skeletal anomalies. Analysis of patients with 4p deletions has identified two WHS critical regions (WHSCRs); however, deletions targeting mouse WHSCRs do not recapitulate the classical WHS defects, and the genes contributing to WHS have not been conclusively established. Recently, the human FGFRL1 gene, encoding a putative fibroblast growth factor (FGF) decoy receptor, has been implicated in the craniofacial phenotype of a WHS patient. Here, we report that targeted deletion of the mouse Fgfrl1 gene recapitulates a broad array of WHS phenotypes, including abnormal craniofacial development, axial and appendicular skeletal anomalies, and congenital heart defects. Fgfrl1 null mutants also display a transient foetal anaemia and a fully penetrant diaphragm defect, causing prenatal and perinatal lethality. Together, these data support a wider role for Fgfrl1 in development, implicate FGFRL1 insufficiency in WHS, and provide a novel animal model to dissect the complex aetiology of this human disease.
Catela
Catarina
C
European Molecular Biology Laboratory, Mouse Biology Unit, Monterotondo, Italy.
Bilbao-Cortes
Daniel
D
Slonimsky
Esfir
E
Kratsios
Paschalis
P
Rosenthal
Nadia
N
Te Welscher
Pascal
P
D000483:Alleles; D000740:Anemia / Q000150:complications; D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones / Q000002:abnormalities / Q000473:pathology; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D006330:Heart Defects, Congenital / Q000150:complications; D006346:Heart Septum / Q000196:embryology; D006351:Heart Valves / Q000196:embryology; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D010920:Placenta / Q000196:embryology; D051500:Receptor, Fibroblast Growth Factor, Type 5 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D012727:Sex Characteristics; D054877:Wolf-Hirschhorn Syndrome / Q000150:complications / Q000473:pathology*
C496379:Fgfrl1 protein, mouse; D051500:Receptor, Fibroblast Growth Factor, Type 5