Multiple congenital malformations of Wolf-Hirschhorn syndrome are recapitulated in Fgfrl1 null mice

• Published in: Disease models & mechanisms Vol. 2; no. 5-6; pp. 283 - 294
• Main Authors: Catela, Catarina, Bilbao-Cortes, Daniel, Slonimsky, Esfir, Kratsios, Paschalis, Rosenthal, Nadia, Te Welscher, Pascal
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.05.2009; The Company of Biologists Limited
• Subjects: Alleles; Anemia - complications; Animals; Animals, Newborn; Bone and Bones - abnormalities; Bone and Bones - pathology; Cartilage; Chromosomes; Embryo, Mammalian - abnormalities; Embryo, Mammalian - pathology; Female; Fetus - abnormalities; Fetus - pathology; Fibroblasts; Gene Expression Regulation, Developmental; Gene Targeting; Genes; Genomes; Genotype & phenotype; Growth factors; Heart Defects, Congenital - complications; Heart Septum - embryology; Heart Valves - embryology; Homozygote; Kinases; Ligands; Mice; Mice, Knockout; Morphology; Patients; Placenta - embryology; Receptor, Fibroblast Growth Factor, Type 5 - deficiency; Receptor, Fibroblast Growth Factor, Type 5 - genetics; Receptor, Fibroblast Growth Factor, Type 5 - metabolism; Recombination, Genetic - genetics; Rodents; Sequence Homology, Nucleic Acid; Sex Characteristics; Signal transduction; Wolf-Hirschhorn Syndrome - complications; Wolf-Hirschhorn Syndrome - pathology; Zebrafish
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.002287

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.