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Lindsay, Mark

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Lindsay

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Mark

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Lindsay, Mark
Author's Publications: search.filters.isAuthorOfPublication.7c4e8131-ed0e-4a6c-ac09-de8d9c1a5a84

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    A mutation update on the LDS‐associated genes TGFB2/3 and SMAD2/3
    (John Wiley and Sons Inc., 2018) Schepers, Dorien; Tortora, Giada; Morisaki, Hiroko; MacCarrick, Gretchen; Lindsay, Mark; Liang, David; Mehta, Sarju G.; Hague, Jennifer; Verhagen, Judith; van de Laar, Ingrid; Wessels, Marja; Detisch, Yvonne; van Haelst, Mieke; Baas, Annette; Lichtenbelt, Klaske; Braun, Kees; van der Linde, Denise; Roos‐Hesselink, Jolien; McGillivray, George; Meester, Josephina; Maystadt, Isabelle; Coucke, Paul; El‐Khoury, Elie; Parkash, Sandhya; Diness, Birgitte; Risom, Lotte; Scurr, Ingrid; Hilhorst‐Hofstee, Yvonne; Morisaki, Takayuki; Richer, Julie; Désir, Julie; Kempers, Marlies; Rideout, Andrea L.; Horne, Gabrielle; Bennett, Chris; Rahikkala, Elisa; Vandeweyer, Geert; Alaerts, Maaike; Verstraeten, Aline; Dietz, Hal; Van Laer, Lut; Loeys, Bart
    Abstract The Loeys–Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor‐β (TGF‐β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF‐β signaling. More recently, TGF‐β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF‐β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF‐β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.
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    An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm
    (Nature Publishing Group UK, 2018) Lino Cardenas, Christian; Kessinger, Chase; Cheng, Yisha; MacDonald, Carolyn; MacGillivray, Thomas; Ghoshhajra, Brian; Huleihel, Luai; Nuri, Saifar; Yeri, Ashish; Jaffer, Farouc; Kaminski, Naftali; Ellinor, Patrick; Weintraub, Neal L.; Malhotra, Rajeev; Isselbacher, Eric; Lindsay, Mark
    Thoracic aortic aneurysm (TAA) has been associated with mutations affecting members of the TGF-β signaling pathway, or components and regulators of the vascular smooth muscle cell (VSMC) actomyosin cytoskeleton. Although both clinical groups present similar phenotypes, the existence of potential common mechanisms of pathogenesis remain obscure. Here we show that mutations affecting TGF-β signaling and VSMC cytoskeleton both lead to the formation of a ternary complex comprising the histone deacetylase HDAC9, the chromatin-remodeling enzyme BRG1, and the long noncoding RNA MALAT1. The HDAC9–MALAT1–BRG1 complex binds chromatin and represses contractile protein gene expression in association with gain of histone H3-lysine 27 trimethylation modifications. Disruption of Malat1 or Hdac9 restores contractile protein expression, improves aortic mural architecture, and inhibits experimental aneurysm growth. Thus, we highlight a shared epigenetic pathway responsible for VSMC dysfunction in both forms of TAA, with potential therapeutic implication for other known HDAC9-associated vascular diseases.
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    A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome
    (eLife Sciences Publications, Ltd, 2015) Doyle, Jefferson J; Doyle, Alexander J; Wilson, Nicole K; Habashi, Jennifer P; Bedja, Djahida; Whitworth, Ryan E; Lindsay, Mark; Schoenhoff, Florian; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Ehsan, Hamid; Huso, David; Thomas, Craig J; Caulfield, Mark J; Van Eyk, Jennifer E; Judge, Daniel P; Dietz, Harry C; Farrar, Carrie
    Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents. DOI: http://dx.doi.org/10.7554/eLife.08648.001
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    Embryonic Development of the Bicuspid Aortic Valve
    (2016) Martin, Peter S.; Kloesel, Benjamin; Norris, Russell A.; Lindsay, Mark; Milan, David; Body, Simon
    Bicuspid aortic valve (BAV) is the most common congenital valvular heart defect with an overall frequency of 0.5%–1.2%. BAVs result from abnormal aortic cusp formation during valvulogenesis, whereby adjacent cusps fuse into a single large cusp resulting in two, instead of the normal three, aortic cusps. Individuals with BAV are at increased risk for ascending aortic disease, aortic stenosis and coarctation of the aorta. The frequent occurrence of BAV and its anatomically discrete but frequent co-existing diseases leads us to suspect a common cellular origin. Although autosomal-dominant transmission of BAV has been observed in a few pedigrees, notably involving the gene NOTCH1, no single-gene model clearly explains BAV inheritance, implying a complex genetic model involving interacting genes. Several sequencing studies in patients with BAV have identified rare and uncommon mutations in genes of cardiac embryogenesis. But the extensive cell-cell signaling and multiple cellular origins involved in cardiac embryogenesis preclude simplistic explanations of this disease. In this review, we examine the series of events from cellular and transcriptional embryogenesis of the heart, to development of the aortic valve.