Friday, August 30, 2013

Molecular etiology of human aortic aneurysm

Research of Mark Evan Lindsay, MD, PhD

Mark Evan Lindsay, MD, PhD; Lecturer on Pediatrics, Massachusetts General Hospital for Children and Harvard Medical School
Mark Evan Lindsay, MD, PhD; Lecturer on Pediatrics, Massachusetts General Hospital for Children and Harvard Medical School.

In addition to performing evaluations for pediatric and adult patients with Marfan syndrome and affiliated disorders within the MGHfC division of Pediatric Cardiology and the MGH Thoracic Aortic Center, Mark Lindsay MD, PhD, conducts clinical and basic science research of aortic disease.


Our laboratory is primarily interested in the clinical expression and molecular etiology of human aortic aneurysm. Aneurysm represents the anatomic expression of aortic organ failure with dilation and eventual tear; an event termed “dissection” associated with high mortality. In our research we use human and murine genetics as well as animal modeling to investigate the etiology and pathologic progression of inherited and sporadic aortic disease. Through our findings we hope to discover better diagnostics and novel therapies for patients with aneurysmal conditions.


Aortic aneurysm is a common human phenotype affecting children and adults that accounts for 1% of death in the industrialized world (Figure 1). The major risk of aortic aneurysm derives not from the presence of aneurysmal dilation but rather to the associated risk of aortic dissection. Dissection is characterized by tearing of the aortic wall, an event with a high mortality rate. Risk factors for aortic dissection include such factors as hypertension, atherosclerosis, and cigarette smoking. While the risk for dissection is multifactoral, one major risk factor is underlying genetic predisposition towards aneurysm. The identification of genes directly associated with aortic aneurysm in humans has allowed for insight into pathologic processes and signaling pathways that mediate disease progression.

Several human conditions have been recognized that associate closely with risk of aortic aneurysm. These conditions transmit faithfully through families and most commonly show autosomal dominant inheritance. The prototypical human genetic condition associated with aortic aneurysm is the Marfan syndrome (MFS), a systemic disorder of connective tissue with primary manifestations in the ocular, skeletal, and cardiovascular systems. MFS is an autosomal dominant human genetic disorder occurring in about one of every 5000 live births, due to mutations in the gene FBN1 encoding fibrillin-1(1). Due to its genetic simplicity and frequency in the human population MFS represents an ideal disorder for research inquiry in syndromic and nonsyndromic aneurysm conditions. Research into the pathogenesis of Marfan syndrome has elucidated the involvement of the TGF-β signaling cascade in the progression of human aortic aneurysm(2). In turn this knowledge has lead to the identification of mutations in genes involved in TGF-β signaling as causal in other human conditions associated with aortic aneurysm including Loeys-Dietz syndrome (caused by mutations in the genes TGFBR1, TGFBR2, SMAD3, and TGFB2)(3-5) and Shprintzen-Goldberg syndrome (caused by mutations in the gene SKI)(6). Each of these genes encode positive regulators of TGF-β signaling, however paradoxically samples from patients with these conditions show a tissue signature compatible with TGF-β upregulation. Disentangling this paradox remains one of the key questions in aneurysm biology(7). 

Gene Discovery

Our understanding of genetic susceptibility to aortic disease has progressed greatly over the last two decades with novel genes described at a rapidly increasing pace. We are highly invested in the discovery of new genes conferring susceptibility to aortic aneurysm in humans. For this purpose, in partnership with Dr. Eric Isselbacher, M.D. (Co-director of the MGH Thoracic Aortic Center), we are actively characterizing individual patients and families affected by aortic disease. To date over 400 individuals with aortic disease have been recruited to join this effort by donating their time and genomic information. In the laboratory we are utilizing traditional and next generation DNA sequencing approaches coupled with a large linked clinical dataset to identify and characterize new genes involved in human aortic disease and the clinical behavior and characteristics of these conditions.

If you are interested in learning about or participating in aortic research at MGH please contact:

Linda Pitler, RN


Mouse models of human aneurysm conditions such as MFS have been developed that recapitulate multiple disease manifestations, importantly including aortic aneurysm, allowing for observations of disease progression to be made across the lifespan. In our lab we utilize animal and cell biological models to investigate the effects of genetic derangements on the performance of aortic cells and their attendant effects on organ function. We are interested in the common pathophysiologic events leading to aortic aneurysm in syndromic and nonsyndromic human conditions. A guiding principle in our approach is to model human disease as closely as possible to make observations that can inform clinical medicine. Our approach integrates murine and human genetics, cardiovascular dynamics, histologic, and cell biologic techniques (Figure 2).

Aortic root aneurysm
Aortic root aneurysm


  1. H. C. Dietz et al., Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352, 337 (Jul 25, 1991)
  2. E. R. Neptune et al., Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 33, 407 (Mar, 2003).
  3. B. L. Loeys et al., A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 37, 275 (Mar, 2005).
  4. .I. M. van de Laar et al., Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet 43, 121 (Feb, 2011).
  5. M. E. Lindsay et al., Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet 44, 922 (2012).
  6. A. J. Doyle et al., Mutations in the TGF-Ҡrepressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nature Genetics, (2012).
  7. M. E. Lindsay, H. C. Dietz, Lessons on the pathogenesis of aneurysm from heritable conditions. Nature 473, 308 (May 19, 2011)

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