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

Nat Genet. 2006 Mar;38(3):343-9. doi: 10.1038/ng1721. Epub 2006 Jan 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Aneurysm, Dissecting / genetics*
  • Aortic Aneurysm, Thoracic / genetics*
  • Base Sequence
  • Ductus Arteriosus, Patent / genetics*
  • Female
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Myosin Heavy Chains / genetics*
  • Pedigree
  • Protein Structure, Secondary

Substances

  • MYH11 protein, human
  • Myosin Heavy Chains

Associated data

  • OMIM/130050
  • OMIM/154700
  • RefSeq/NM_002474
  • RefSeq/NM_022870
  • RefSeq/NP_002465
  • RefSeq/NP_074035