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.

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

“…Our results also suggest that genetic testing and cardiac imaging with at least TTE should be offered to all FDRs and SDRs of patients with suspected NS‐TADs. Mutation carriers should undergo further imaging (MRI or CT scan), focusing on thoracic aorta and/or other arterial trees based on the causative gene mutation 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74. For example, ACTA2‐mutation carriers should be monitored for coronary artery disease and occlusive cerebrovascular disease, in addition to the currently recommended routine imaging tests 32.…”

“…First, variable penetrance, which often characterizes NS‐TAD forms, is a potential confounder. This results in intrafamilial variability, which is evident not only with reference to the aortopathy itself (severity, age of onset), but also with regard to other phenotypic manifestations 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81. The presence of associated features is certainly suggestive of having inherited the aortic condition along with the predisposition to the aortopathy, but the absence of these associated features does not eliminate the risk of having an underlying aortopathy.…”

Phenotypic expansion of visceral myopathy associated with ACTG2 tandem base substitution

“…[1][2][3] The first genes associated with smooth muscle myopathy were MYH11 and ACTA2, both of which encode components of the contractile sarcomere, in families with thoracic aortic dissections (TAADs; MIM: 132900 and 611788). 4,5 Later, variants in ACTA2 were shown to be associated with multisystemic smooth muscle dysfunction syndrome (MIM: 613834) and a broad phenotypic spectrum. 6,7 A group among the visceral myopathies comprises the enteric visceral myopathies characterized predominantly by impaired gastrointestinal propulsion resulting in pain, distention, malabsorption and even death.…”

Compliance and pulse wave velocity assessed by MRI detect early aortic impairment in young patients with mutation of the smooth muscle myosin heavy chain

“…2 (4). This syndrome was caused by mutations in the MYH11 gene in both the "Bourgogne family" and an American kindred (5). These mutations affect in a dominant-negative manner the dimerization of the C-terminal coiled-coil region of the smooth muscle myosin heavy chain.…”