Feb. 27, 2001 A multi-center team of researchers has discovered a possible genetic cause of infant lung disease. They found that two patients who developed a potentially fatal form of lung disease within the first months of life both had a mutation of one of the genes responsible for producing pulmonary surfactant, a material in the lungs that keeps them inflated. The study is reported in the Feb. 22 issue of the New England Journal of Medicine.
"These fundamental investigations will allow us to develop more sophisticated therapies for respiratory problems," says Aaron Hamvas, M.D., associate professor of pediatrics at Washington University School of Medicine in St. Louis. "We now are one step closer to identifying another type of genetic lung disease, but we still have a long way to go."
Hamvas, who also serves on the staff of St. Louis Children’s Hospital, is a collaborator in this study along with researchers at the University of Cincinnati and Johns Hopkins University. The first author is Lawrence M. Nogee, M.D., of Johns Hopkins University School of Medicine.
These three institutions have investigated hundreds of cases of lung disease from around the world in an effort to better understand the underlying causes of the disease. Such was the case with the mother-daughter pair described in this report. Both mother and daughter had no breathing difficulties at birth but subsequently developed interstitial lung disease. The exact number of chronic lung disorders in this disease category still is unknown.
Diagnosed as a toddler, the mother was treated throughout her childhood and adolescence. She died of respiratory failure shortly after the birth of her child.
Her infant girl developed lung disease at 6 weeks old. A family history revealed that the baby’s maternal grandfather also died of life-long lung disease.
The tiny air sacs responsible for gas exchange in the lungs are called alveoli. These are lined with a thin layer of fluid, called surfactant, to prevent the walls of the alveoli from sticking together and collapsing during exhalation. Without enough surfactant, the lungs lose their elasticity and breathing becomes difficult.
Researchers found that tissue samples from both mother and baby lacked one component of surfactant called surfactant protein C, or SP-C. DNA analysis revealed that both had a mutation in the gene for this protein. The gene was not mutated in DNA samples from 50 healthy patients.
The findings suggest that SP-C is important for normal lung function after birth and that mutations in this gene may be associated with interstitial lung disease.
In 1993, researchers at Washington University School of Medicine discovered a lethal genetic lung disease in newborns characterized by a lack of another component of surfactant, SP-B. Newborns with this disease now survive with the help of a lung transplant.
"The identification of the SP-B deficiency has opened a new area of investigation for newborn lung disease and suggests that there are genetic causes of respiratory distress in newborns," Hamvas says. "This has led physicians and scientists around the country to be much more aggressive in trying to diagnose and understand these breathing disorders."
The current SP-C research holds similar promise for lung disease that develops in infants or older children.
DNA analysis of the mother and daughter pair also revealed that the genetic mutation is a dominant trait, found on only one gene. This means a child may have symptoms even if only one parent has the mutation. Most other lung diseases, including SP-B deficiency, result from recessive traits, where patients must inherit the same mutation from both parents in order for the disease to appear. The identification of SP-C gene mutations as a possible cause of interstitial lung disease may provide for more accurate classification of the many conditions within this disease category. It also may lead to improved diagnostic techniques – such as a blood test, rather than invasive procedures like lung biopsy – and better treatments, such as gene therapy.
Nogee LM, Dunbar AE, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the surfactant protein C (SP-C) gene associated with familial interstitial lung disease. New England Journal of Medicine, Feb. 22, 2001.
The research was supported by grants from the National Institutes of Health and the Eudowood Foundation.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
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