Preliminary Evidence for Aortopathy and an X-Linked Parent-of-Origin Effect on Aortic Valve Malformation in a Mouse Model of Turner Syndrome - PubMed (original) (raw)

Preliminary Evidence for Aortopathy and an X-Linked Parent-of-Origin Effect on Aortic Valve Malformation in a Mouse Model of Turner Syndrome

Robert B Hinton et al. J Cardiovasc Dev Dis. 2015.

Abstract

Turner syndrome (TS), most frequently caused by X-monosomy (45,X), is characterized in part by cardiovascular abnormalities, including aortopathy and bicuspid aortic valve (BAV). There is a need for animal models that recapitulate the cardiovascular manifestations of TS. Extracellular matrix (ECM) organization and morphometrics of the aortic valve and proximal aorta were examined in adult 39,XO mice (where the parental origin of the single X was paternal (39,XPO) or maternal (39,XMO)) and 40,XX controls. Aortic valve morphology was normal (tricuspid) in all of the 39,XPO and 40,XX mice studied, but abnormal (bicuspid or quadricuspid) in 15% of 39,XMO mice. Smooth muscle cell orientation in the ascending aorta was abnormal in all 39,XPO and 39,XMO mice examined, but smooth muscle actin was decreased in 39,XMO mice only. Aortic dilation was present with reduced penetrance in 39,XO mice. The 39,XO mouse demonstrates aortopathy and an X-linked parent-of-origin effect on aortic valve malformation, and the candidate gene FAM9B is polymorphically expressed in control and diseased human aortic valves. The 39,XO mouse model may be valuable for examining the mechanisms underlying the cardiovascular findings in TS, and suggest there are important genetic modifiers on the X chromosome that modulate risk for nonsyndromic BAV and aortopathy.

Keywords: 39,XO; FAM9B; Xlr3b; cardiovascular malformation; disease models; genomic imprinting; heritability; valves.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Aortic valve morphology is abnormal in 39,XMO mice only. Aortic valves and proximal aortas are shown in the long axis view in adult 40,XX wild type controls (A) 39,XPO (B) and 39,XMO (C) mice. Trilaminar extracellular matrix (ECM) organization in both aortic valve and aorta tissue is preserved in 39, XO mice (B,C). Normal aortic valve morphology is seen in the short axis view in 40,XX (D) and 39,XPO mice (E), i.e., a tricuspid pattern with three commissures (yellow arrowheads); however, 39,XMO mice demonstrate a variety of malformation patterns, including bicuspid aortic valve (BAV), as evidenced by two commissures (F), and quadricuspid aortic valve, which shows four commissures (G). Panels shown at 20× magnification; scale bar 250 μm.

Figure 2

Figure 2

Aorta smooth muscle cell orientation is abnormal in both 39,XMO and 39,XPO mice, but content is decreased in 39,XMO mice only. High magnification of the ascending aorta in adult 40,XX wild type controls (A) 39,XPO (B) and 39,XMO (C) mice demonstrate intact elastic fiber architecture and subtle smooth muscle cell misalignment abnormalities in both 39,XPO and 39,XMO mice. Note the plane of the smooth muscle cells in the 39, XO mice (yellow arrowheads) is orthogonal to the plane of elastic fibers, when compared with the normal parallel orientation of the cells (yellow arrowheads in panel H). SMA staining shows normal diffuse expression in 40,XX (D) aortas, as well as 39,XPO (E) aortas despite the cell orientation abnormality, but significantly decreased expression in 39,XMO mice (F). Panels are shown at 100×; scale bar 25 μm.

Figure 3

Figure 3

FAM9B is polymorphically expressed in human aortic valve tissue. FAM9B is expressed in control (No BAV, No AVD) human aortic valve tissue; however, there is no clear relationship between FAM9B expression (black arrowhead at ~275 bp) status, when compared with positive control expression from a human FAM9B cDNA clone (left columns), and aortic valve morphology (tricuspid or bicuspid), the presence of aortic valve disease (pediatric or adult), or gender (male or female). Samples were run simultaneously two per group (black bars), except BAV aAVD Male due to a technical failure (lane 12), and beta-actin (ACTB) was used as the housekeeping gene. BAV bicuspid aortic valve; AVD aortic valve disease; p: pediatric; a: adult; loading control (lane 3).

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