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PMID:19383940

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Citation

Catela, C, Bilbao-Cortes, D, Slonimsky, E, Kratsios, P, Rosenthal, N and Te Welscher, P Multiple congenital malformations of Wolf-Hirschhorn syndrome are recapitulated in Fgfrl1 null mice. Dis Model Mech 2:283-94

Abstract

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.

Links

PubMed PMC2675798 Online version:10.1242/dmm.002287

Keywords

Alleles; Anemia/complications; Animals; Animals, Newborn; Bone and Bones/abnormalities; Bone and Bones/pathology; Embryo, Mammalian/abnormalities; Embryo, Mammalian/pathology; Female; Fetus/abnormalities; Fetus/pathology; Gene Expression Regulation, Developmental; Gene Targeting; Heart Defects, Congenital/complications; Heart Septum/embryology; Heart Valves/embryology; Homozygote; Mice; Mice, Knockout; 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; Sequence Homology, Nucleic Acid; Sex Characteristics; Wolf-Hirschhorn Syndrome/complications; Wolf-Hirschhorn Syndrome/pathology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:FGRL1

acts_upstream_of_or_within

GO:0001501: skeletal system development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3849002

P

  • results_in_development_of:(EMAPA:17214)|results_in_development_of:(EMAPA:19019)|results_in_development_of:(EMAPA:18028)

Seeded From UniProt

complete

MOUSE:FGRL1

acts_upstream_of_or_within

GO:0003179: heart valve morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3849002

P

Seeded From UniProt

complete

MOUSE:FGRL1

acts_upstream_of_or_within

GO:0060412: ventricular septum morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3849002

P

Seeded From UniProt

complete


See also

References

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