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Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus


We have recently described two kindreds presenting thoracic aortic aneurysm and/or aortic dissection (TAAD) and patent ductus arteriosus (PDA)1,2 and mapped the disease locus to 16p12.2-p13.13 (ref. 3). We now demonstrate that the disease is caused by mutations in the MYH11 gene affecting the C-terminal coiled-coil region of the smooth muscle myosin heavy chain, a specific contractile protein of smooth muscle cells (SMC). All individuals bearing the heterozygous mutations, even if asymptomatic, showed marked aortic stiffness. Examination of pathological aortas showed large areas of medial degeneration with very low SMC content. Abnormal immunological recognition of SM-MHC and the colocalization of wild-type and mutant rod proteins in SMC, in conjunction with differences in their coimmunoprecipitation capacities, strongly suggest a dominant-negative effect. Human MYH11 gene mutations provide the first example of a direct change in a specific SMC protein leading to an inherited arterial disease.

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Figure 1: MYH11 mutations in the French kindred.
Figure 2: MYH11 mutation in the American kindred.
Figure 3: Structural and immunolabeling abnormalities of the aortic tissue.
Figure 4: Characterization of SM-MHC in the aortic tissue by immunoblotting.
Figure 5: In vitro assay of the interaction between wild-type and mutant SM-MHC rod.

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We thank all the affected individuals and their families participating in this study. We thank the clinical research groups of Dijon University Hospital, the Conseil Régional de Bourgogne, the Fondation pour la Recherche Médicale, the Association Claude Bernard, the Leducq Foundation for their support. Experiments have also benefited from the facilities of the Institut de Biologie at the Collège de France and the Institut Federatif de Recherche at Faculté Bichat. We also thank C. Delaloy, E. Etienne, J. Hadchouel, J. Favier, O. Meilhac, A.M. Houot, L. Muller, C. Pouzet for technical help and advice, M. David for surgical aortic samples and M.-T. Zabot for primary cultures of fibroblasts. P. Khau Van Kien was funded by the Association de Cardiologie de Bourgogne. L. Zhu was funded by the Association Claude Bernard and then by the Programme Charcot of the French Foreign Ministry.

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Correspondence to Xavier Jeunemaitre.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Characteristics of the 16 relatives with MYH11 mutation. (PDF 20 kb)

Supplementary Table 2

Characteristics of the 33 relatives without MYH11 mutation. (PDF 19 kb)

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Zhu, L., Vranckx, R., Van Kien, P. et al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet 38, 343–349 (2006).

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