Myosin heavy chain 11, a novel gene for thoracic aortic aneurysm/dissection

A mutation in the myosin heavy chain 11 gene has been found to be responsible for a syndrome associated with aortic aneurysm/dissection and patent ductus arteriosus referred to as TADD.

The myosin heavy chain 11 gene is located on chromosome 16p12.2-13.3. Three previous loci have been mapped: 11q23-24, 5q13-14 and 3p24-25. The currently identified myosin gene encodes for a contractile protein found in the smooth muscle of blood vessels. The mutations occur in the C-terminus of the coiled-coil region.

In a French pedigree, two heterozygous mutations were identified in MYH11. The first was a substitute mutation that occurs in a splice junction of intron 32 (IVS32+IGT). Messenger RNA extracted from cultured fibroblasts of affected subjects showed that exon 32 was missing, resulting in a frame shift of 71 amino acids in the C-terminal region of the MYH11 protein.

Robert Roberts

The second, a missense mutation, was identified in exon 37 (G5361A). This mutation resulted in a charged amino acid, arginine, being replaced by a noncharged amino acid, glutamine (R1758Q).

Both mutations were identified in all subjects with the disease haplotype, but neither was found in 340 normal chromosomes.

A similar search in an American kindred found another substitution with a deletion of 72 nucleotides in exon 28 of the MYH11 gene that was not detected in 340 normal chromosomes. This in-frame deletion corresponds to the lost of 24 amino acids in the C-terminal region of the MYH11 protein.

The smooth muscle myosin molecule (MYH11) is composed of two heavy chains (SM-MHC), two essential light chains and two regulatory light chains. The C-terminal end of this molecule consists of a series of heptad repeats with alternating positive and negative charges that are essential for rod assembly and thick filament formation. Thus, it is expected these mutations may prevent or impair assembly of myosin thick filaments into the formation of a sarcomere.

The mutations were inherited as autosomal dominant. The predominant phenotype is thoracic aortic aneurysm with or without dissection and an accompanying patent ductus arteriosus. All individuals heterozygous for the mutation — even if asymptomatic — had marked aortic stiffness. The pathology consisted of large areas of medial necrosis with very low smooth muscle cell content.

Immunological detection showed co-localization of the mutant and wild type myosin heavy chain 11 (MYH11) in smooth muscle cells. The pathology is keeping with a dominant negative effect, but would have to be confirmed by in vitro or in vivo functional analysis.

Nat Genet. 2006;38:343-349.

Robert Roberts, MD, is President and CEO of the University of Ottawa Heart Institute and a section editor of Cardiology Today’s Molecular Cardiology section.