Delineation and Therapeutic Implications of a Modifier Locus of Aortic Aneurysm in Marfan Syndrome. A. Doyle1,2,3, J. Doyle1, K. Kent1, L. Myers1, N. Wilson1, N. Huso1, D. Bedja4,5, M. Lindsay6, J. Pardo-Habashi1,7, B. Loeys8, J. De Backer9, A. De Paepe9, H. Dietz1,2,7 1) Institute of Genetic Medicine, Johns Hopkins Medical Institute, Baltimore, MD, USA; 2) Howard Hughes Medical Institute, Baltimore, MD, USA; 3) William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK; 4) Department of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 5) Australian School of Advanced Medicine, Macquarie University, Sydney, Australia; 6) Massachusetts General Hospital Thoracic Aortic Center, Departments of Medicine and Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 7) Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 8) Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium; 9) Centre of Medical Genetics, Ghent University Hospital, Ghent, Belgium.

   Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the FBN1 gene. The major cause of mortality is aortic aneurysm, dissection and rupture. While the disorder shows high penetrance, there is also variable expression, which has been attributed to extreme allelic heterogeneity as well as variation dictated by the level of expression of the wild-type FBN1 allele. There is a growing body of evidence that promiscuous activation of TGF is responsible for multiple manifestations of the disease and that specific inhibition of the angiotensin II type 1 receptor (AT1R) and/or mitogen activated protein kinase (MAPK; JNK or ERK1/2) activation can ameliorate aortic aneurysm. We previously reported identification of a major protective modifier locus for MFS, encompassing a 5.5Mb linkage interval on chromosome 6 (LOD= 4.0), using 5 exceptional families with defined and typical FBN1 mutations showing discrete intrafamilial variation in the penetrance of vascular disease. While the protective haplotype varied between families, all patients with mild disease (20/20) shared a 3.9Mb familial haplotype that was only observed in 2/18 severely affected family members (p<0.0001). Of the 32 genes in the linkage interval, 2 emerged as strong candidates based on known function; MAS1 encoding the receptor for Ang1-7, a natural antagonist of AT1R signaling, and MAP3K4, a MAPK kinase kinase and effector of noncanonical TGF signaling. To date, direct sequencing of all exons and flanking intron boundaries has not identified causative variation. In the absence of additional families to narrow the linkage interval, we turned to functional analyses in a validated mouse model of MFS that shows fully penetrant postnatal aneurysm progression (Fbn1C1039G/+). Targeted disruption of a single Map3k4 allele was sufficient to fully normalize the aortic root growth rate to wild-type levels in Fbn1C1039G/+ mice (p<0.01). Similarly, systemic administration of Ang1-7 (the endogenous MAS1 receptor ligand) to Fbn1C1039G/+ mice not only prevented abnormal aortic root and ascending aortic growth when compared to untreated mutant littermates (p<0.001 for both comparisons) but also induced a significant regression in the absolute aortic root size (p<0.001) over a 3-month time period. These results provide further evidence of a protective locus on the distal arm of chromosome 6 and indicate that both MAP3K4 and MAS1 represent novel therapeutic targets in patients with MFS.

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