Genetics of Hereditary Large Vessel Diseases

Abstract

Recently, the genetic study of hereditary large vessel diseases such as Marfan syndrome has been advanced, leading to not only identifying pathogenic genes but also providing information of the pathophysiology and possible new therapeutic targets. Genes identified for hereditary large vessel diseases include FBN1 , TGFBR1 , TGFBR2 , SMAD3 , TGFB2 , TGFB3 , SKI , EFEMP2 , BGN , COL3A1 , FLNA , ACTA2 , MYH11 , MYLK , SLC2A10 and NOTCH1 . Dysfunction of these genes is mainly connected with altered function of transforming growth factor‐β (TGF‐β) signalling pathways, as well as that of the extracellular matrix or smooth muscle contractile apparatus, resulting in progression of structural abnormality to aorta and large vessels including aortic aneurysms and dissections. Furthermore, it has been shown that the TGF‐β signalling pathway plays a key role in the pathogenesis of Marfan syndrome and Loeys–Dietz syndrome, which may be important for development of strategies for medical and surgical treatment of hereditary large vessel diseases. Key Concepts Genetic study of hereditary large vessel diseases has been advanced. Young patients with large vessel diseases should be aware of possible genetic disease. Alteration of transforming growth factor‐β (TGF‐β) signalling pathways as well as that of the extracellular matrix or smooth muscle contractile apparatus is closely connected with large vessel diseases. Genetic study of hereditary large vessel diseases may help to get better therapeutic approach in the near future. Medical treatment modulating TGF‐β signaling would be effective for hereditary large vessel diseases.

Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients

“…4 Three main pathomechanisms have emerged for hereditary aortopathies: (1) abnormal extracellular matrix assembly and maintenance/homeostasis, (2) increased TGF-β signaling, and (3) disruption of the vascular smooth muscle cell contractile apparatus. 5,6 Accordingly, most known genes implicated in hereditary aortopathies encode structural connective tissue proteins such as collagens and fibrillins, enzymes involved in the biosynthesis or processing of structural connective tissue proteins (e.g., PLOD1), TGF-β signaling proteins (e.g., TGFBR1, SMAD3), or regulators and components of the cytoskeleton (e.g., MYH11). 3 Connective tissue is found in different organs, thus a genetic alteration in a single HCTD-related disease gene can manifest in several body systems.…”

Novel Insights into the Aortic Mechanical Properties of Mice Modeling Hereditary Aortic Diseases

“…In humans, these three genes ( LTBP1 , MFAP4 , and TIMP1 ) are expressed at higher levels in arterial tissue than in any other tissue studied in GTEx (gtexportal.org/home). LTBP1 interacts with ECM proteins, such as MFS-associated FBN1, and regulates transforming growth factor (TGF)-β, 50 which plays an important role in the pathogenesis of hADs. 51 MFAP4, an ECM protein found in elastic fibers, interacts with FBN1, FBN2, and type I collagen as well as actively promotes tropoelastin self-assembly by binding tropoelastin.…”

Left main coronary artery compression by a dilated main pulmonary artery and left coronary sinus of Valsalva aneurysm in a patient with heritable pulmonary arterial hypertension and FLNA mutation

“…FLNA encodes filamin A, an actin-binding protein that is involved in remodeling the cytoskeleton to effect changes in cell shape and migration. Mutation in FLNA causes multiple malformation syndromes, [17][18][19][20] including periventricular nodular heterotopias, otopalatodigital syndromes, frontometaphyseal dysplasia, Melnick-Needles syndrome, X-linked congenital idiopathic intestinal pseudoobstruction, and Ehlers-Danlos spectrum. Recently there have been several reports of a relationship between FLNA mutations and cardiovascular complications, including valvular insufficiency, carotid dissection, and thoracic aortic dilatation and dissection.…”