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Johns Hopkins Medicine
Office of Corporate Communications
Media Contact: Joanna Downer
October 28, 2004


At the annual meeting of the American Society of Human Genetics, to be held Oct 27 to Oct. 30 in Toronto, researchers and clinicians of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins will present their latest detective work on conditions ranging from high blood pressure to cystic fibrosis and Marfan syndrome. The advances described below also reflect the important contributions of Hopkins' trainees: the predoctoral students and postdoctoral fellow who conducted the work were nominated for -- and two of them won -- research awards from the ASHG. Find the abstracts from these and other Hopkins researchers on the ASHG Web site at (registration is not necessary).

Genetic Cause of a Cystic Fibrosis-Like Disease Identified

Researchers from the McKusick-Nathans Institute of Genetic Medicine and elsewhere have identified the genetic underpinnings of a condition whose symptoms overlap those of cystic fibrosis.

Cystic fibrosis (CF) is characterized by cellular problems in the transport of chloride and sodium, which creates infection-harboring mucus build-up in the lungs, and is caused by mutations in a gene called CFTR. Because of sodium's role in CF, the researchers decided to see if genes for a sodium channel might harbor disease-causing mutations in some people with CF-like disease but no CFTR mutations.

By sequencing the three genes that encode the three parts of a particular sodium channel in samples from 23 patients, graduate student Molly Sheridan and her colleagues discovered three disease-causing mutations. Sheridan is scheduled to present the findings at 9 a.m., Oct. 28, at the ASHG annual meeting in Toronto.

"One of the mutations we found in the sodium channel genes rendered the channel nonfunctional when we tested it in the lab, and we expect based on sequence information that the other two mutations we identified would also disrupt the channel's function," says Sheridan, who won the American Society of Human Genetics Predoctoral Clinical Research Award for the work.

The genes the researchers investigated, known as ENaC for epithelial sodium channel, had already been tied to a condition called pseudohypoaldosteronism, in which problems predominate in the kidney. The researchers' new work suggests that some disruptions of ENaC can alter the channels' abilities without erasing them, leading to symptoms like lung disease that look more like CF, says the study's senior author, Garry Cutting, M.D., professor in the McKusick-Nathans Institute.

Sheridan is a doctoral candidate in the Cellular and Molecular Medicine graduate program at Johns Hopkins. The research was funded by the Cystic Fibrosis Foundation, the National Heart, Lung and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Center for Research Resources, part of the National Institutes of Health.


Growth Factor Is Behind Heart Problems in Marfan Syndrome

 Marfan syndrome has long been tied to mutations in a gene called fibrillin-1, but Hopkins researchers now report that the well-known protein transforming growth factor beta (TGF-beta) is directly responsible for the syndrome's deleterious effects on heart valves.

Marfan syndrome is a disorder of the body's connective tissues -- the material that gives other tissues form and strength. Common characteristics of the syndrome are unusually tall height, long limbs and fingers, and eye and heart problems. If the syndrome's heart valve and aortic problems aren't caught early and surgically repaired, the condition can be deadly in childhood.

All people with Marfan syndrome have mutations in one copy of their fibrillin-1 gene that reduces the amount of fibrillin-1 protein that cells can make. Unfortunately, that knowledge has proved diagnostic but not therapeutic. However, Hopkins researchers Enid Neptune, M.D., Harry (Hal) Dietz, M.D., and their colleagues discovered in 2003 that fibrillin-1 deficiency in mice heightens activation of TGF-beta, which directly causes lung problems that lead to emphysema.

Now, Harvard medical student Connie Ng, Dietz and colleagues report that excessive TGF-beta activity is also behind problems with the heart's mitral valve in mice with Marfan syndrome. In experiments with mice missing fibrillin-1, the researchers found that excessive TGF-beta activity was present at the locations of valve distortion. Importantly, blocking TGF-beta's activity in young mice prevented the deadly damage from occurring.

"TGF-beta is a target for preventing death due to Marfan syndrome, because its activity is directly responsible for at least two important problems seen in the condition," says Dietz, professor in the McKusick-Nathans Institute of Genetic Medicine, a Howard Hughes Medical Institute investigator and director of the William S. Smilow Center for Marfan Syndrome Research at Johns Hopkins. "We still have a lot of work to do before we can start clinical trials of TGF-beta inhibitors in people with Marfan syndrome, but it's very exciting to have a real target for medical, rather than surgical, treatment of the condition." 

Ng conducted the research during her year as a Sarnoff fellow working in Dietz's lab at Hopkins and is scheduled to present the findings at 10 a.m. ET, Oct. 28, at the annual meeting of the American Society of Human Genetics. She was a semifinalist for a Predoctoral Basic Research Award from the society. The research was funded by The Sarnoff Endowment for Cardiovascular Science, the Howard Hughes Medical Institute, The Smilow Foundation, and the National Institutes of Health.


Genes on Chromosome 1 Behind Mysterious Cases of High Blood Pressure

Johns Hopkins researchers have discovered that a region of chromosome 1 contains genes that contribute to "essential hypertension," or cases of high blood pressure that appear without a predisposing condition, such as kidney disease.

Such mysterious cases of high blood pressure are thought to stem from problems with the kidney's normal balancing of sodium in the blood, but genetic contributors to this common condition are unknown. Postdoctoral fellow Yen-Pei Christy Chang, Ph.D., and her team studied samples from 1,875 people representing 585 families. Detailed genetic analysis linked the condition to a region of chromosome 1 that contains hundreds of genes.

"By using information from the Human Genome Project and conducting more in-depth genetic analysis of this region, we narrowed down the likely genes to approximately 30," says Chang, who received a Postdoctoral Clinical Research Award from the American Society of Human Genetics for this work. "Looking even closer, we've found significant and consistent association of disease with variants of just three genes, quite a manageable number to investigate further."

The region of chromosome 1 has also been flagged by two other large studies, but this is the first report of individual genes that are associated with blood pressure regulation and susceptibility to high blood pressure. One of the three genes identified plays a known role in the kidney's absorption of sodium, and the other identified genes are likely to affect blood vessels' ability to react to changes in blood pressure, says principal investigator Aravinda Chakravarti, Ph.D., professor and director of the McKusick-Nathans Institute of Genetic Medicine.

Chang is scheduled to present the work at 2:30 p.m., Oct. 28, at the annual meeting of the American Society of Human Genetics in Toronto. The research was funded by the National Institutes of Health.        



On the Web:

Earlier work on TGF-beta in Marfan syndrome: