NEW YORK (Reuters Health) - Researchers have evidence linking a founder mutation (R674Q) in the perinatal myosin heavy chain gene (MYH8) to a novel heart-hand syndrome characterized by cardiac myxomas and distal arthrogryposis.
“No one has ever suspected that changes in muscle myosin could be involved in tumor formation,” Dr. Craig T. Basson, from Weill Medical College of Cornell University, in New York, told Reuters Health. “Our findings demonstrate novel roles for perinatal myosin in both the development of skeletal muscle and cardiac tumorigenesis,” he and colleagues write in the July 29th issue of The New England Journal of Medicine.
Familial cardiac myxomas are a component of the Carney complex, a familial autosomal dominant multiple neoplasia syndrome. Previously, Dr. Basson and others found that mutations in the PRKAR1A gene, which encodes the R1-alpha subunit of cAMP-dependent protein kinase A, can cause the Carney complex (See Reuters Health report August 11, 2000). Still, the disorder is “genetically heterogeneous,” the investigators emphasize.
In the NEJM this week, Dr. Basson’s group describes a large kindred with the Carney complex in which affected individuals not only had cardiac myxomas but also a rare hereditary muscle disorder characterized by abnormal hand and jaw contractions called trismus-pseudocamptodactyly syndrome, or TPC.
Through genetic analysis they were able to link this variant form of the Carney complex (CNC-TPC) to chromosome 17p12-p13.1 and sequence analysis revealed the R674Q missense mutation in the MYH8 gene. This mutation was not present in unaffected family members and linkage to PRKAR1A was excluded.
The researchers found the same R674Q mutation of the MYH8 gene in two other families with the TPC syndrome.
From a clinical perspective, the identification of this MYH8 “founder mutation in patients with CNC-TPC should prompt future assessment of the risk of cardiac myxomas in patients with the trismus-pseudocamptodactyly syndrome,” the researchers conclude.
For now, Dr. Basson said patients with the TPC syndrome be “considered at risk for developing a heart tumor” and undergo surveillance echocardiography annually.
In an editorial, Dr. Jil C. Tardiff from Albert Einstein College of Medicine in the Bronx, New York writes that the genetic linkage of cardiac myxomas to distal arthrogryposis is both “unexpected and exciting.”
It’s possible, she theorizes, that the perinatal myosin heavy chain is “an important component of the developmental pathway that determines the number of native cardiac progenitor cells in the developing heart.”
Perhaps the R674Q mutation in the perinatal myosin heavy chain blocks the loss of these “multipotent cells so that affected patients end up carrying a larger population through adulthood, with the concomitant increased risk of a ‘second hit’ that would lead to primary cardiac tumorigenesis.”
Clearly, Dr. Tardiff admits, this report raises many more questions than it answers. However, it is “abundantly clear, " in her opinion, “that we must once again readjust our thinking and broaden our horizons regarding the multifunctional roles of myosins in human biology.”
Source: N Engl J Med 2004;351:424-426,460-469. [ Google search on this article ]
MeSH Headings:Heart Neoplasms: Neoplasms: Neoplasms by Site: Thoracic Neoplasms: DiseasesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
