Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm

Helen B Taussig Children's Heart Center, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nature Genetics (Impact Factor: 29.35). 07/2012; 44(8):922-7. DOI: 10.1038/ng.2349
Source: PubMed


Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.

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    • "Since degradation of the vascular wall in aortic aneurysms is related to disturbances in the TGF-β signaling pathway [14], [21], we next investigated the role of TGF-β signaling in alveolar wall degradation in Fibulin-4 deficient mice. Although the gene expression analysis in lung mRNA samples only gave rise to a limited set of deregulated genes in newborn Fibulin-4R/R animals, it did reveal downregulation of the Pias4 gene in Fibulin-4R/R compared to Fibulin-4+/+ lungs (1.2-fold, p<0.05, "
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    ABSTRACT: Background In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an inherited deficiency of connective tissue might play a role in the combined development of pulmonary emphysema and vascular disease. Methods We first determined the prevalence of chronic obstructive pulmonary disease in a clinical cohort of aortic aneurysms patients and arterial occlusive disease patients. Subsequently, we used a combined approach comprising pathological, functional, molecular imaging, immunological and gene expression analysis to reveal the sequence of events that culminates in pulmonary emphysema in aneurysmal Fibulin-4 deficient (Fibulin-4R) mice. Results Here we show that COPD is significantly more prevalent in aneurysm patients compared to arterial occlusive disease patients, independent of smoking, other clinical risk factors and inflammation. In addition, we demonstrate that aneurysmal Fibulin-4R/R mice display severe developmental lung emphysema, whereas Fibulin-4+/R mice acquire alveolar breakdown with age and upon infectious stress. This vicious circle is further exacerbated by the diminished antiprotease capacity of the lungs and ultimately results in the development of pulmonary emphysema. Conclusions Our experimental data identify genetic susceptibility to extracellular matrix degradation and secondary inflammation as the common mechanisms in both COPD and aneurysm formation.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "The TGFB2 gene is also involved with Loyes-Dietz syndrome 4 (OMIM #614816) caused by heterozygous mutation in the TGFB2 gene. Lindsay et al. [18] identified two unrelated patients with aortic aneurysm and de novo 1q41 microdeletions encompassing the TGFB2, one with Marfan syndrome and the other with Loyes-Dietz syndrome-like features. The RYR2 gene, which maps to 1q42q43, encodes a ryanodine receptor found in cardiac muscle. "
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    ABSTRACT: Background Partial duplication 1q is a rare cytogenetic anomaly frequently associated to deletion of another chromosome, making it difficult to define the precise contribution of the different specific chromosomal segments to the clinical phenotype. Case presentation We report a clinical and cytogenomic study of a patient with multiple congenital anomalies, heart defect, neuromotordevelopment delay, intellectual disability, who presents partial trisomy 1q32 and partial monosomy 11q25 inherited from a paternal balanced translocation identified by chromosome microarray and fluorescence in situ hybridization. Conclusion Compared to patients from the literature, the patient’s phenotype is more compatible to the 1q32 duplication’s clinical phenotype, although some clinical features may also be associated to the deleted segment on chromosome 11. This is the smallest 11q terminal deletion ever reported and the first association between 1q32.3 duplication and 11q25 deletion in the literature.
    Full-text · Article · Aug 2014 · Molecular Cytogenetics
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    • "Indeed, the Loeys Dietz syndrome is linked with mutations within the genes encoding TGF-β receptors type I or II (TGFBR1 or TGFBR2) [4]. Subsequently, mutations in the SMAD3 [5] and TGFB2 [6], [7] genes were identified. Mutations in the gene encoding Smad3 in autosomal dominant TAAD patients were recently associated with early onset osteoarthritis, defining a new entity: Aneurysms Osteoarthritis Syndrome (AOS) [5]. "
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    ABSTRACT: Severe osteoarthritis and thoracic aortic aneurysms have recently been associated with mutations in the SMAD3 gene, but the full clinical spectrum is incompletely defined. All SMAD3 gene mutation carriers coming to our centre and their families were investigated prospectively with a structured panel including standardized clinical workup, blood tests, total body computed tomography, joint X-rays. Electroneuromyography was performed in selected cases. Thirty-four SMAD3 gene mutation carriers coming to our centre were identified and 16 relatives were considered affected because of aortic surgery or sudden death (total 50 subjects). Aortic disease was present in 72%, complicated with aortic dissection, surgery or sudden death in 56% at a mean age of 45 years. Aneurysm or tortuosity of the neck arteries was present in 78%, other arteries were affected in 44%, including dissection of coronary artery. Overall, 95% of mutation carriers displayed either aortic or extra-aortic arterial disease. Acrocyanosis was also present in the majority of patients. Osteoarticular manifestations were recorded in all patients. Joint involvement could be severe requiring surgery in young patients, of unusual localization such as tarsus or shoulder, or mimicking crystalline arthropathy with fibrocartilage calcifications. Sixty eight percent of patients displayed neurological symptoms, and 9 suffered peripheral neuropathy. Electroneuromyography revealed an axonal motor and sensory neuropathy in 3 different families, very evocative of type II Charcot-Marie-Tooth (CMT2) disease, although none had mutations in the known CMT2 genes. Autoimmune features including Sjogren's disease, rheumatoid arthritis, Hashimoto's disease, or isolated autoantibodies- were found in 36% of patients. SMAD3 gene mutations are associated with aortic dilatation and osteoarthritis, but also autoimmunity and peripheral neuropathy which mimics type II Charcot-Marie-Tooth.
    Full-text · Article · May 2014 · PLoS ONE
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