Corporate Banner
Satellite Banner
Scientific Community
Become a Member | Sign in
Home>News>This Article

New Genetic Cause of Pulmonary Hypertension Identified

Published: Thursday, July 25, 2013
Last Updated: Thursday, July 25, 2013
Bookmark and Share
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. 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.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,800+ scientific posters on ePosters
  • More than 4,000+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

New Link Between Obesity and Diabetes Found
Targeting a single enzyme that raises both sugar and insulin levels in the obese could prevent and treat diabetes.
Monday, November 25, 2013
Is There a Role for Vitamins in Cancer Prevention?
According to recent national surveys, approximately 40 percent of U.S. adults take multivitamins/multiminerals.
Monday, August 12, 2013
Study Reveals Genes That Drive Brain Cancer
About 15 percent of glioblastoma patients could receive personalized treatment with drugs currently used in other cancers.
Tuesday, August 06, 2013
Key Molecular Pathways Leading to Alzheimer’s Identified
Research approach highlights potential therapeutic targets.
Thursday, July 25, 2013
Mutation Linked to Congenital Urinary Tract Defects
Findings point to new diagnostic category.
Thursday, July 18, 2013
Mouse Study Suggests Lead May Trigger Schizophrenia
Behavioral and MRI study in mice points to a synergistic relationship between lead exposure and schizophrenia gene.
Monday, June 10, 2013
Many Birth Defects in Heart Caused by Spontaneous Mutations
A study has found that at least 10 percent of cases stem from genetic mutations that occur spontaneously early in development.
Thursday, May 30, 2013
Common Childhood Asthma Not Rooted in Allergens, Inflammation
Discovery of origins of a unique form of asthma may lead to a precision medicine approach to treatment.
Friday, May 24, 2013
Looking for the Telltale Gene
A new genetic test allows parents to peer into their unborn children's medical future.
Friday, May 24, 2013
Hundreds of Alterations and Potential Drug Targets to Starve Tumors Identified
A massive study analyzing gene expression data from 22 tumor types has identified multiple metabolic expression changes associated with cancer.
Monday, April 22, 2013
New Gene Associated with Almost Doubled Alzheimer’s Risk in African-Americans
ABCA7, a minor gene variant in whites, is major player in African-Americans.
Wednesday, April 10, 2013
Schizophrenia Gene Networks Found, and a Link to Autism
Although schizophrenia is highly genetic in origin, the genes involved in the disorder have been difficult to identify.
Thursday, November 15, 2012
New de novo Genetic Mutations in Schizophrenia Identified
Columbia University Medical Center (CUMC) researchers have identified dozens of new spontaneous genetic mutations that play a significant role in the development of schizophrenia, adding to the growing list of genetic variants that can contribute to the disease.
Thursday, October 04, 2012
New de novo Genetic Mutations in Schizophrenia Identified
Columbia University Medical Center (CUMC) researchers have identified dozens of new spontaneous genetic mutations that play a significant role in the development of schizophrenia, adding to the growing list of genetic variants that can contribute to the disease.
Thursday, October 04, 2012
Tom Maniatis: A Deep Sense that Science Must Be Shared
History books are filled with the technical advances that made genetic engineering possible, from the discovery of enzymes that cut and paste DNA to the development of techniques for reading the sequence of genes.
Tuesday, September 11, 2012
Scientific News
New Tech Vastly Improves CRISPR/Cas9 Accuracy
A new CRISPR/Cas9 technology developed by scientists at UMass Medical School is precise enough to surgically edit DNA at nearly any genomic location, while avoiding potentially harmful off-target changes typically seen in standard CRISPR gene editing techniques.
New Class of RNA Tumor Suppressors Identified
Two short, “housekeeping” RNA molecules block cancer growth by binding to an important cancer-associated protein called KRAS. More than a quarter of all human cancers are missing these RNAs.
Biologists Induce Flatworms to Grow Heads and Brains of Other Species
Findings shed light on role of a new kind of epigenetic signaling in evolution, could yield clues for understanding birth defects and regeneration.
Turning up the Tap on Microbes Leads to Better Protein Patenting
Mining millions of proteins could become faster and easier with a new technique that may also transform the enzyme-catalyst industry, according to University of California, Davis, researchers.
Mathematical Model Forecasts the Path of Breast Cancer
Chances of survival depend on which organs breast cancer tumors colonize first.
Exploring the Causes of Cancer
Queen's research to understand the regulation of a cell surface protein involved in cancer.
Ancient Viral Molecules Essential for Human Development
Genetic material from ancient viral infections is critical to human development, according to researchers at the Stanford University School of Medicine.
Tardigrade's Are DNA Master Thieves
Tardigrades, nearly microscopic animals that can survive the harshest of environments, including outer space, hold the record for the animal that has the most foreign DNA.
The Secret Behind the Power of Bacterial Sex
Migration between different communities of bacteria is the key to the type of gene transfer that can lead to the spread of traits such as antibiotic resistance, according to researchers at Oxford University.
Farming’s in Their DNA
Ancient genomes reveal natural selection in action.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos