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Case Reports
. 2022 Dec;15(6):e003707.
doi: 10.1161/CIRCGEN.122.003707. Epub 2022 Nov 9.

Further Evidence That ARIH1 Rare Variants Predispose to Thoracic Aortic Disease

Maura L Boerio  1 , Nicole M Engelhardt  2 , Sanmati Cuddapah  2 , Jessica I Gold  2 , Isabella C Marin  1 , Amélie Pinard  1 , Dongchuan Guo  1 , Siddharth K Prakash  1 , Dianna M Milewicz  1
Affiliations
Case Reports

Further Evidence That ARIH1 Rare Variants Predispose to Thoracic Aortic Disease

Maura L Boerio et al. Circ Genom Precis Med. 2022 Dec.
No abstract available

Keywords: aneexome; aneurysm, dissecting; aortic aneurysm; genetic heterogeneity; mutation.

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Figures

Figure 1.
Figure 1.
ARIH1 rare variants alter nuclear envelope morphology and predispose to thoracic aortic disease. A. Echocardiographic image of the 8-year-old child with the de novo ARIH1 variant, illustrating fusiform dilatation of the aortic root (2.5 cm; z-score 3.1) and ascending aorta (2.5 cm; z-score 4.2). B. Transmission electron microscopy of a normal nuclear envelope of aortic SMC from a control (left panel) and irregularly shaped nuclear envelopes in aortic SMCs from patients with ARIH1 rare variants (right two panels). Reprinted from Developmental Cell, volume 45, Tan et al., Ari-1 Regulates Myonuclear Organization Together with Parkin and Is Associated with Aortic Aneurysms, pages 226–244, Copyright 2018, with permission from Elsevier. C. Schematic of the ARIH1 protein with the location of rare variants in ARIH1 associated with thoracic aortic disease indicated. Novel variants reported here are in red. Gly-rich, glycine rich; UBA-like, ubiquitin associated-like; IBR, in between RING. D. SMC contractile units, composed of actin thin filaments and myosin thick filaments, link to proteins in the ECM through integrin receptors. Altered genes that predispose to HTAD disrupt proteins in the contractile units or ECM, including FBN1, ACTA2 and MYH11. Contractile units also link to the nuclear envelope through the LINC complex. ARIH1 regulates the LINC complex by mono-ubiquitinating SUN2. LoF or rare variants in ARIH1 lead to irregular nuclear envelope morphology, which potentially disrupts the ability of the LINC complex to connect to actin thin filaments in the contractile units, and thus predisposes to thoracic aortic disease. Created with BioRender.com. ECM, extracellular matrix; LINC, linker of nucleoskeleton and cytoskeleton; ONM, outer nuclear membrane; PNS, perinuclear space; INM, inner nuclear membrane.
See this image and copyright information in PMC

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