title: Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus.
abstract: We have recently described two kindreds presenting thoracic aortic aneurysm and/or aortic dissection (TAAD) and patent ductus arteriosus (PDA) 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.
authors.affiliation: Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Département de Génétique, 75015 Paris, France.
authors.forename: Limin
authors.initials: L
authors.lastname: Zhu
authors.forename: Roger
authors.initials: R
authors.lastname: Vranckx
authors.forename: Philippe
authors.initials: P
authors.lastname: Khau Van Kien
authors.forename: Alain
authors.initials: A
authors.lastname: Lalande
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boisset
authors.forename: Flavie
authors.initials: F
authors.lastname: Mathieu
authors.forename: Mark
authors.initials: M
authors.lastname: Wegman
authors.forename: Luke
authors.initials: L
authors.lastname: Glancy
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Gasc
authors.forename: François
authors.initials: F
authors.lastname: Brunotte
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.forename: Jean-Eric
authors.initials: JE
authors.lastname: Wolf
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000784:Aortic Dissection / Q000235:genetics*; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics*; D001483:Base Sequence; D004374:Ductus Arteriosus, Patent / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D010375:Pedigree; D017433:Protein Structure, Secondary
chemical_list: C509903:MYH11 protein, human; D018995:Myosin Heavy Chains