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Pathogenic effect of a TGFBR1 mutation in a family with Loeys-Dietz syndrome.

ABSTRACT: BACKGROUND:Thoracic aortic aneurysms and dissections (TAAD) may have a heritable cause in up to 20% of cases. We aimed to investigate the pathogenic effect of a TGFBR1 mutation in relation to TAAD. METHODS:Co-segregation analysis was performed followed by functional investigations, including myogenic transdifferentiation. RESULTS:The c.1043G>A TGFBR1 mutation was found in the index patient, in a deceased brother, and in five presymptomatic family members. Evidence for pathogenicity was found by the predicted damaging effect of this mutation and the co-segregation in the family. Functional analysis with myogenic transdifferentiation of dermal fibroblasts to smooth muscle-like cells, revealed increased myogenic differentiation in patient cells with the TGFBR1 mutation, shown by a higher expression of myogenic markers ACTA2, MYH11 and CNN1 compared to cells from healthy controls. CONCLUSION:Our findings confirm the pathogenic effect of the TGFBR1 mutation in causing TAAD in Loeys-Dietz syndrome and show increased myogenic differentiation of patient fibroblasts.

SUBMITTER: Cozijnsen L

PROVIDER: S-EPMC6785444 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Pathogenic effect of a TGFBR1 mutation in a family with Loeys-Dietz syndrome.

Cozijnsen Luc L Plomp Astrid S AS Post Jan G JG Pals Gerard G Bogunovic Natalija N Yeung Kak K KK Niessen Hans W M HWM Goumans Marie-José T H MTH Barge-Schaapveld Daniela Q C M DQCM Micha Dimitra D

Molecular genetics & genomic medicine 20190901 10

<h4>Background</h4>Thoracic aortic aneurysms and dissections (TAAD) may have a heritable cause in up to 20% of cases. We aimed to investigate the pathogenic effect of a TGFBR1 mutation in relation to TAAD.<h4>Methods</h4>Co-segregation analysis was performed followed by functional investigations, including myogenic transdifferentiation.<h4>Results</h4>The c.1043G>A TGFBR1 mutation was found in the index patient, in a deceased brother, and in five presymptomatic family members. Evidence for patho ...[more]

PMID: 31475485

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Project description:Background and purposeLoeys-Dietz syndrome (LDS) is a recently described entity that has the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Its neuroradiologic manifestations have not been well delineated. We sought to describe the neuroradiologic features of LDS and to assess the manifestations that would warrant follow-up imaging.Materials and methodsTwo neuroradiologists retrospectively reviewed CT angiography (CTA), MR imaging, and plain film studies related to the head and neck in 25 patients ranging from 1 to 55 years of age, all of whom had positive genetic testing and clinical characteristics of LDS. Arterial tortuosity was evaluated by subjective assessment of 2D and 3D volumetric CTA and MR angiography data. Craniosynostosis and spinal manifestations were assessed by using plain films and CT images. MR images mostly of the head were reviewed for associated findings such as hydrocephalus, Chiari malformation, etc. Clinical manifestations were collated from the electronic patient record.ResultsAll patients had extreme arterial tortuosity, which is characteristic of this syndrome. Thirteen patients had scoliosis, 12 had craniosynostosis, 8 had intracranial aneurysms, 6 had spinal instability, 3 had dissections of the carotid and vertebrobasilar arteries, 3 had hydrocephalus, 4 had dural ectasia, 2 had a Chiari malformation, and 1 had intracranial hemorrhage as a complication of vascular dissection.ConclusionsSignificant neuroradiologic manifestations are associated with LDS, predominantly arterial tortuosity. Most of the patients in this series were young and, therefore, may require serial CTA monitoring for development of intra- and extracranial dissections and aneurysms, on the basis of the fact that most of the patients with pseudoaneurysms and dissection were older at the time of imaging. Other findings of LDS such as craniosynostosis, Chiari malformation, and spinal instability may also need to be addressed.

Dataset Information

Pathogenic effect of a TGFBR1 mutation in a family with Loeys-Dietz syndrome.

Publications

Pathogenic effect of a TGFBR1 mutation in a family with Loeys-Dietz syndrome.

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