Absence of cardiovascular manifestations in a haploinsufficient Tgfbr1 mouse model.
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...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2014
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/b75c363598d6443c995fbd08ab7f6f85 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:b75c363598d6443c995fbd08ab7f6f85 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:b75c363598d6443c995fbd08ab7f6f852021-11-18T08:31:17ZAbsence of cardiovascular manifestations in a haploinsufficient Tgfbr1 mouse model.1932-620310.1371/journal.pone.0089749https://doaj.org/article/b75c363598d6443c995fbd08ab7f6f852014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24587008/?tool=EBIhttps://doaj.org/toc/1932-6203Loeys-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.Marjolijn RenardBram TrachetChristophe CasteleynLaurence CampensPieter CornillieBert CallewaertSteven DeleyeBert VandeghinstePaula M van HeijningenHarry DietzFilip De VosJeroen EssersSteven StaelensPatrick SegersBart LoeysPaul CouckeAnne De PaepeJulie De BackerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 2, p e89749 (2014) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Marjolijn Renard Bram Trachet Christophe Casteleyn Laurence Campens Pieter Cornillie Bert Callewaert Steven Deleye Bert Vandeghinste Paula M van Heijningen Harry Dietz Filip De Vos Jeroen Essers Steven Staelens Patrick Segers Bart Loeys Paul Coucke Anne De Paepe Julie De Backer Absence of cardiovascular manifestations in a haploinsufficient Tgfbr1 mouse model. |
| description |
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. |
| format |
article |
| author |
Marjolijn Renard Bram Trachet Christophe Casteleyn Laurence Campens Pieter Cornillie Bert Callewaert Steven Deleye Bert Vandeghinste Paula M van Heijningen Harry Dietz Filip De Vos Jeroen Essers Steven Staelens Patrick Segers Bart Loeys Paul Coucke Anne De Paepe Julie De Backer |
| author_facet |
Marjolijn Renard Bram Trachet Christophe Casteleyn Laurence Campens Pieter Cornillie Bert Callewaert Steven Deleye Bert Vandeghinste Paula M van Heijningen Harry Dietz Filip De Vos Jeroen Essers Steven Staelens Patrick Segers Bart Loeys Paul Coucke Anne De Paepe Julie De Backer |
| author_sort |
Marjolijn Renard |
| title |
Absence of cardiovascular manifestations in a haploinsufficient Tgfbr1 mouse model. |
| title_short |
Absence of cardiovascular manifestations in a haploinsufficient Tgfbr1 mouse model. |
| title_full |
Absence of cardiovascular manifestations in a haploinsufficient Tgfbr1 mouse model. |
| title_fullStr |
Absence of cardiovascular manifestations in a haploinsufficient Tgfbr1 mouse model. |
| title_full_unstemmed |
Absence of cardiovascular manifestations in a haploinsufficient Tgfbr1 mouse model. |
| title_sort |
absence of cardiovascular manifestations in a haploinsufficient tgfbr1 mouse model. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/b75c363598d6443c995fbd08ab7f6f85 |
| work_keys_str_mv |
AT marjolijnrenard absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT bramtrachet absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT christophecasteleyn absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT laurencecampens absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT pietercornillie absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT bertcallewaert absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT stevendeleye absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT bertvandeghinste absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT paulamvanheijningen absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT harrydietz absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT filipdevos absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT jeroenessers absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT stevenstaelens absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT patricksegers absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT bartloeys absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT paulcoucke absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT annedepaepe absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel AT juliedebacker absenceofcardiovascularmanifestationsinahaploinsufficienttgfbr1mousemodel |
| _version_ |
1718421705025650688 |