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Familial aortic dissection due to mutations in MLCK
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It is estimated that approximately 20% of patients with thoracic aortic disease have a family history suggesting an inherited predisposition.
The usual type of inheritance is autosomal dominant with variable penetrance and expression. The latter indicates that, even with the mutant gene, the percentage of those who will develop the disease is variable, and those in whom disease develops, the associated clinical features are variable. The typical natural history is gradual enlargement of the thoracic aorta (aneurysm), which predisposes to acute dissection and rupture. Although the dissection, when it occurs, is frequently associated with rupture and sudden death, it is often prevented by surgically repairing the dilated aorta before dissection.
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Mutations linked to aortic dilatation
Several mutations that cause aortic dilatation have been identified in alpha-actin and beta-myosin heavy chain genes, which encode for corresponding proteins known to be involved with smooth muscle contraction. In a recent study, Wang and colleagues at The University of Texas in Houston sequenced several candidate genes known to be important in smooth muscle contraction, including myosin light chain kinase (MLCK), calmodulin (CAL) and regulatory myosin light chain (RLC).
These genes were sequenced in 94 affected probands from unrelated families in which two or more members had thoracic aortic aneurysms or aortic dissections. The researchers identified a missense mutation in the MLCK gene at nucleotide position 5275, in which a thymine (T) substituted for cytosine (C) in one family was designated as cT5275C. This mutation was shown to induce an amino acid change in the protein at the position designated as pS1759P, in which the amino acid serine (S) substitutes for the amino acid proline (P).
The MLCK gene was then sequenced in an additional 99 probands, and four other missense mutations were identified. These missense mutations were also shown to induce changes in the amino acids of the protein MLCK. None of these mutations were present in the 188 matched controls. All of the families are small, so they did not lend themselves to genome-wide linkage analysis, which is the typical approach. The approach adopted here is referred to as the candidate-gene approach and, as such, has an inherent bias. Combining the LOD score of four families, they obtained a combined score of only 2.1 (P=.0009). Thus, there is the necessity to seek other evidence before one can conclude these mutations induce aortic dissection.
Mutations and smooth muscle contraction
Utilizing two mutations (p.S1759P and p.A1754T) in the MLCK, functional studies were also performed in isolated cells. The wild and mutant forms of these two MLCK mutations were expressed in COS cells. These study results suggested that the mutant genes encoded abnormalities in the protein, which lead to decreased binding of the CAL complex to the MLCK. The influx of calcium, which triggers smooth muscle contraction, binds to CAL and forms a complex by binding to MLCK enzyme. This, ultimately, induces contraction of the smooth muscle. Decreased binding of the MLCK to the calcium CAL complex resulted in impaired contraction, as one would expect. Expression of the wild and mutant forms of the MLCK in the mouse did not show a phenotype of aortic dissection but was associated with the accumulation of proteoglycans in the aorta, which is the early finding preceding aortic dilatation and subsequent dissection.
Study implications
The findings in this study, although using the candidate-gene approach as opposed to the conventional genome-wide linkage analysis, provide strong evidence that at least two of the mutations identified are responsible for aortic dissection. The findings in support of this conclusion are as follows: The mutations are expressed in the protein and disrupt a binding site for the calcium CAL complex; the mutations, despite the small families, segregate only in those affected with the disease; these mutations were not present in any of the normal 188 controls; and expression in intact cells was associated with impaired smooth muscle contraction.
An important clinical finding of these mutations in MLCK is related to the observed phenotype of the families. These four families have an unusual phenotype in that the aortic dissection and rupture occurred without prior dilatation, which is often fatal. Thus, these mutations could be used to identify those at risk. The genetics of aortic aneurysm and dissection are gradually being unraveled as these several mutations are being identified.
Robert Roberts, MD, is the president and CEO of the University of Ottawa Heart Institute and director of the Ruddy Canadian Cardiovascular Genetics Centre at the University of Ottawa Heart Institute.
For more information:
- Wang L. Am J Hum Genet. 2010:87;701-707.