Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New genetic cause of pulmonary hypertension identified

25.07.2013
Study finds druggable target for rare fatal lung disease

Columbia University Medical Center (CUMC) scientists have identified new genetic mutations that can cause pulmonary arterial hypertension (PAH), a rare fatal disease characterized by high blood pressure in the lungs.


This is a cross section of a potassium channel in a smooth muscle cell of the pulmonary artery. A study by Dr. Wendy Chung has identified six new mutations in a gene called KCNK3 that can interfere with the function of potassium channels and lead to pulmonary hypertension. The mutations are depicted in color at the locations where they exert their effects.

Credit: Columbia University Medical Center

The mutations, found in the gene KCNK3, appear to affect potassium channels in the pulmonary artery, a mechanism not previously linked to the condition. Cell culture studies showed that the mutations' effects could be reversed with a drug compound known as a phospholipase inhibitor. The study was published today in the online edition of the New England Journal of Medicine.

"The most exciting thing about our study is not that we've identified a new gene involved in pulmonary hypertension, but that we've found a drug that can 'rescue' some mutations," said co-senior author Wendy K. Chung, MD, PhD, associate professor of pediatrics and medicine at CUMC. "In genetics, it's common to identify a gene that is the source of a disease. However, it's relatively rare to find potential treatments for genetic diseases."

PAH is a progressive disorder characterized by abnormally high blood pressure in the pulmonary artery, which reduces blood flow from the right side of the heart to the lungs. The heart can compensate by pumping harder, but over time this can weaken the heart muscle and lead to right-sided heart failure. Common symptoms of PAH include shortness of breath, dizziness, and fainting. About 1,000 new cases are diagnosed in the United States each year. The disorder is twice as common in females as in males. There is no cure for PAH and few effective treatments. Most patients with PAH die within 5–7 years of diagnosis.

Some cases of PAH are caused by inherited genetic defects. Most of these "familial" cases have been linked to mutations in a gene called BMPR2 (bone morphogenetic protein receptor, type II), which was identified simultaneously in 2000 by two independent research teams, one led by the late Robin Barst and Jane Morse, CUMC researchers. However, the majority of cases are idiopathic in origin (of unknown cause). Other forms of PAH can be triggered by autoimmune diseases, congenital heart defects, infections (such as schistosomiasis), and medications (such as the now-banned diet-drug combination commonly known as fen-Phen).

Dr. Chung and her colleagues discovered the new mutations by sequencing the exomes (the portion of the genome that codes information to make proteins) of families with PAH without identified mutations. KCNK3 mutations were found in 3.2 percent of those with familial disease and in 1.3 percent of those with idiopathic PAH.

The team found that the mutations alter the function of potassium channels by reducing the activity of these channels. Potassium channels help maintain the vascular tone of the pulmonary artery and help it respond to low levels of oxygen.

"We were surprised to learn that KCNK3 appears to play a role in the function of potassium channels in the pulmonary artery," said Dr. Chung. "No one had suspected that this mechanism might be associated with PAH." The other gene linked to the disorder, BMPR2, is thought to cause PAH by ultimately promoting growth and multiplication of smooth muscle cells in the pulmonary artery, thereby restricting blood flow.

Dr. Chung also found, working in collaboration with co-senior author, Robert S. Kass, PhD, the Alumni and David Hosack Professor of Pharmacology, chair of the department, and vice dean for research at CUMC, that the effects of the KCNK3 mutations could be reversed with an experimental phospholipase inhibitor called ONO-RS-082. The findings were made in cell cultures. Further study is needed to determine whether treatment with this or other drugs that affect potassium channels might be useful in the treatment of people with PAH, said Dr. Chung.

"KCNK3 mutations are a rare cause of PAH, so I don't want to oversell our findings," said Dr. Chung. "Still, it's exciting that we've found a mechanism that can lead to the disease that is a new, druggable target. It's also possible that targeting KCNK3 may be beneficial for patients who have PAH independent of their KCNK3 genetic status."

The paper is titled, "A Novel Channelopathy in Pulmonary Arterial Hypertension." The other contributors are: Lijiang Ma, Danilo Roman-Campos, Eric D, Mélanie Eyries, Kevin Sampson, Florent Soubrier, Marine Germain, David-Alexandre Trégouët, Alain Borczuk, Erika Berman Rosenzweig, Barbara Girerd, David Montani, Marc Humbert, and James E. Loyd.

The authors declare no financial or other conflicts of interests.

The study was supported by grants from the National Institutes of Health (R01 HL060056, P01 HL072058, K23 HL098743, and R01 HL56810) and by a Vanderbilt Clinical and Translational Science Awards (UL1 RR024975) from the National Center for Research Resources.

Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.

Karin Eskenazi | EurekAlert!
Further information:
http://www.columbia.edu

More articles from Life Sciences:

nachricht New application for acoustics helps estimate marine life populations
16.01.2018 | University of California - San Diego

nachricht Unexpected environmental source of methane discovered
16.01.2018 | University of Washington Health Sciences/UW Medicine

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

Im Focus: A thermometer for the oceans

Measurement of noble gases in Antarctic ice cores

The oceans are the largest global heat reservoir. As a result of man-made global warming, the temperature in the global climate system increases; around 90% of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

White graphene makes ceramics multifunctional

16.01.2018 | Materials Sciences

Breaking bad metals with neutrons

16.01.2018 | Materials Sciences

ISFH-CalTeC is “designated test centre” for the confirmation of solar cell world records

16.01.2018 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>