Genetics of Hereditary Large Vessel Diseases


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.

Keywords: aortic aneurysm; aortic dissection; genetics of aortopathy; transforming growth factor‐β (TGF‐β); extracellular matrix; smooth muscle

Figure 1. FBN1 and TGF‐β signalling pathways. Fibrillin‐1 associates with LLC, consisting of LTBP and SLC, and regulates the TGF‐β signalling pathway (Morisaki and Morisaki, ). Active, free TGF‐β molecules will be regulated by protease cleavage of inactive SLC molecules bound to LAP. LLC, large latent complex; SLC, small latent complex; LAP, latency‐associated peptide; LTBP, latent TGF‐β‐binding protein
Figure 2. TGF‐β signalopathies. Several genes (FBN1, TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD3, BGN and SKI) associated with Marfan and related disorders are closely connected with the TGF‐β signalling pathways (Morisaki and Morisaki, ). Changes in the signal regulatory function promote pathological progress of aortic lesions.


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Further Reading

Gillis E, Van Laer L and Loeys BL (2013) Genetics of thoracic aortic aneurysm: at the crossroad of transforming growth factor‐β signaling and vascular smooth muscle cell contractility. Circulation Research 113: 327–340.

Isselbacher EM, Lino Cardenas CL and Lindsay ME (2016) Hereditary Influence in Thoracic Aortic Aneurysm and Dissection. Circulation 133: 2516–2528.

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Milewicz DM, Guo DC, Tran‐Fadulu V, et al. (2008) Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction. Annual Review of Genomics and Human Genetics 9: 283–302.

Pyeritz RE (2014) Heritable thoracic aortic disorders. Current Opinion in Cardiology 29: 97–102.

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Morisaki, Takayuki, and Morisaki, Hiroko(Aug 2017) Genetics of Hereditary Large Vessel Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027328]