title: Absence of cardiovascular manifestations in a haploinsufficient Tgfbr1 mouse model.
abstract: Loeys-Dietz syndrome (LDS) is an autosomal dominant arterial aneurysm disease belonging to the spectrum of transforming growth factor β (TGFβ)-associated vasculopathies. In its most typical form it is characterized by the presence of hypertelorism, bifid uvula/cleft palate and aortic aneurysm and/or arterial tortuosity. LDS is caused by heterozygous loss of function mutations in the genes encoding TGFβ receptor 1 and 2 (TGFBR1 and -2), which lead to a paradoxical increase in TGFβ signaling. To address this apparent paradox and to gain more insight into the pathophysiology of aneurysmal disease, we characterized a new Tgfbr1 mouse model carrying a p.Y378* nonsense mutation. Study of the natural history in this model showed that homozygous mutant mice die during embryonic development due to defective vascularization. Heterozygous mutant mice aged 6 and 12 months were morphologically and (immuno)histochemically indistinguishable from wild-type mice. We show that the mutant allele is degraded by nonsense mediated mRNA decay, expected to result in haploinsufficiency of the mutant allele. Since this haploinsufficiency model does not result in cardiovascular malformations, it does not allow further study of the process of aneurysm formation. In addition to providing a comprehensive method for cardiovascular phenotyping in mice, the results of this study confirm that haploinsuffciency is not the underlying genetic mechanism in human LDS.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Marjolijn
authors.initials: M
authors.lastname: Renard
authors.affiliation: Institute Biomedical Technology - Biofluid, Tissue and Solid Mechanics for Medical Applications, Ghent University, Ghent, Belgium.
authors.forename: Bram
authors.initials: B
authors.lastname: Trachet
authors.affiliation: Department of Morphology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium ; Department of Veterinary Sciences, Faculty of Pharmaceutical, Biochemical and Veterinary Sciences, University of Antwerp, Wilrijk, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Casteleyn
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Campens
authors.affiliation: Department of Morphology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Cornillie
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Callewaert
authors.affiliation: Institute Biomedical Technology - Medical Image and Signal Processing Unit, Ghent University, Ghent, Belgium ; Molecular Imaging Center, University of Antwerp, Wilrijk, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Deleye
authors.affiliation: Institute Biomedical Technology - Medical Image and Signal Processing Unit, Ghent University, Ghent, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Vandeghinste
authors.affiliation: Departments of Cell Biology and Genetics, Radiation Oncology and Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Paula M
authors.initials: PM
authors.lastname: van Heijningen
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Harry
authors.initials: H
authors.lastname: Dietz
authors.affiliation: Laboratory of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: De Vos
authors.affiliation: Departments of Cell Biology and Genetics, Radiation Oncology and Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Essers
authors.affiliation: Institute Biomedical Technology - Medical Image and Signal Processing Unit, Ghent University, Ghent, Belgium ; Molecular Imaging Center, University of Antwerp, Wilrijk, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Staelens
authors.affiliation: Institute Biomedical Technology - Biofluid, Tissue and Solid Mechanics for Medical Applications, Ghent University, Ghent, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Segers
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium ; Center for Medical Genetics, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Loeys
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Coucke
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: De Backer
mesh_terms: D000818:Animals; D018376:Cardiovascular Abnormalities / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics; D004195:Disease Models, Animal; D004452:Echocardiography; D005453:Fluorescence; D005838:Genotype; D057895:Haploinsufficiency / Q000502:physiology*; D007150:Immunohistochemistry; D055947:Loeys-Dietz Syndrome / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D049268:Positron-Emission Tomography; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics; D018709:Statistics, Nonparametric; D055114:X-Ray Microtomography
chemical_list: D018389:Codon, Nonsense; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse