Mutations in Surfactant Proteins Cause Fatal Lung Diseases in Newborns and Children
Mutations in the genes encoding surfactant protein B (SP-B) and surfactant protein C (SP-C) are associated with acute respiratory failure and interstitial lung disease in newborns, children and adults, reports a recent New England Journal of Medicine article authored by Jeffrey Whitsett, MD, and Timothy Weaver, PhD, in the Division of Pulmonary Biology at Cincinnati Children's.
The invited article on "Mechanisms of Disease" summarizes findings generated primarily in the laboratories at Cincinnati Children's over the last 15 years regarding the structure and function of SP-B and SP-C. "These are critical components of surfactant replacement therapy used for treatment of respiratory distress in preterm infants. This work summarizes their roles in pulmonary surfactant necessary for lung function in newborns, children and adults," says Dr. Whitsett.
SP-B Critical for Infant Survival
The researchers have found that SP-B is absolutely required for postnatal survival. "A mutation in the SP-B gene leads to the loss of a protein causing neonatal respiratory distress syndrome. Mutations in the SP-B gene are usually fatal in the newborn period," Dr. Weaver explains.
"If a pediatrician is caring for a full-term newborn with respiratory distress that is resistant to conventional therapies and is without an obvious cause, a mutation in the SP-B gene should be considered. These are rare events, but they happen. Every week we get calls from physicians around the world who are seeing this," he says. Currently, a lung transplant is the only treatment for infants with this mutation. In the future, Dr. Weaver believes that gene therapy will offer hope for intervening in the disease process.
More recently, the researchers and their collaborators identified the role of mutations in the SP-C gene in both childhood and adult lung disease. Mutations in the SP-C gene cause an interstitial lung disease called pulmonary fibrosis. Unlike SP-B, SP-C is not necessary for survival. However, the researchers identified a population of infants and adults with a mutation in the SP-C gene who had developed pulmonary fibrosis, which is also rare.
"This is the first association between mutations in human genes that causeidiopathic, familial, pulmonary fibrosis," Dr. Whitsett says.
Exploring the Role of Genetics
Dr. Weaver notes that the SP-C mutation always causes interstitial lung disease, but not all individuals with the disease have this mutation. "We had suspected a genetic basis for interstitial lung disease. For now, this finding gives us a model to explore the genetic basis of the disease in animals. We are looking for gene targets that would be amenable to therapy. Very long-term, we hope to devise a therapy for patients,"he says.
Mutations in both SP-B and SP-C need additional study, the researchers say, because the diseases they cause are fatal. "The SP-B mutation is usually lethal. If you're born with it, you're almost always going to die. These babies can be kept alive only with heroic measures. Pulmonary fibrosis caused by the SP-C mutation develops much more slowly, but it is devastating and often fatal without a lung transplant," Dr. Weaver explains.
Pioneers in Surfactant Therapy Dr. Whitsett's and Dr. Weaver's research began in the 1980s with the study of lung surfactant and surfactant proteins, their composition and function. That research contributed to the application of surfactant preparations for the treatment of respiratory distress syndrome. Surfactant replacement therapy continues to save the lives of infants around the world.
Their work evolved into the study of the two primary protein components of surfactant, SP-B and SP-C. "Once we knew the composition of surfactant, we started screening patients for deficiencies in these proteins to study their effects," Dr. Weaver says. A key collaborator in their work is Lawrence Nogee, MD, a neonatologist at Johns Hopkins Medicine, Baltimore, Maryland, and a former fellow at Cincinnati Children's.
"These studies provide the basis for understanding the causes of acute and chronic respiratory disease," Dr. Whitsett says. "Such insights are likely to lead to improved diagnosis and new therapies for both acute and chronic lung disease in the future."
This paper was published in The New England Journal of Medicine (347[8]:2141-2148, 2002 December 26) and was supported by grants from the National Institutes of Health.
