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Genetic Mutation Linked to Infant Lung Disease

Johns Hopkins Medicine
Office of Communications and Public Affairs
Media Contact: Jessica Collins
March 24, 2004


Researchers at the Johns Hopkins Children's Center, the Cincinnati
Children's Hospital Medical Center and the National Cancer Institute's Laboratory of Genomic Diversity have discovered a genetic defect associated with a severe and often fatal infant lung disease.

Their findings, reported in this week's New England Journal of Medicine, confirm that mutations in the ABCA3 gene lead to a serious lack of surfactant, a mixture of fats and proteins that enables lung expansion and contraction and maintains the low surface tension needed to prevent lung collapse.

Study co-author Lawrence Nogee, M.D., a neonatologist at the Children's Center, speculates that since the ABCA3 gene is related to a family of transporter proteins, the defective ABCA3 protein may shuttle the phospholipids (compounds of fatty acids, phosphoric acid and a nitrogenous base) critical for surfactant function into the compartment in the cell where surfactant is stored.

"This kind of defective transport could lead to the production of abnormal surfactant, or,alternatively, a mutated ABCA3 gene could fail to transport out lipids toxic to surfactant function," he says.

Researchers zeroed in on ABCA3 as a candidate gene for unexplained surfactant deficiency in full-term infants because of other ABC genes' links with human diseases, the cellular location of ABCA3, and ABCA3's already suspected involvement in transporting lipids, says Nogee.

In the study, researchers first identified 21 infants with severe lung disease and surfactant deficiency of unknown causes, but whose family medical histories suggested a genetic basis for their problems.

Mutations in ABCA3 were found in 16 infants, 15 of whom died of their illness.  Of the five patients without ABCA3 mutations, three infants recovered completely. Two later died from their lung disease.

Nogee notes that because one infant with the ABCA3 mutation survived its initial lung disease, some ABCA3 mutations may not be fatal.

"Our findings provide yet another clue as to what may trigger surfactant deficiency and neonatal lung disease, but the absence of an ABCA3 mutation in at least two infants in our study who developed fatal lung disease indicates that there are still other genes yet to be identified in this disease," Nogee says.

He adds that it is also necessary to study the occurrence of ABCA3 genetic mutations in the general population and determine their variability in order to narrow down which gene variants are harmless and which variants lead to disease.

The study's findings are the latest fruits from a long-standing research collaboration, funded by grants from the National Institutes of Health and the Johns Hopkins Eudowood Foundation. The team has investigated the causes of lung disease in hundreds of patients around the world.

"The study provides new insight into how the lung functions," says the study's senior author, Michael Dean, Ph.D., of the National Cancer Institute's (NCI) Laboratory of Genomic Diversity. "The lung surfactants that ABCA3 helps produce are essential for breathing and this work may provide insight into other pulmonary diseases."

"These advances are made possible by the availability of the gene sequence provided by the human genome project and by close interactions among doctors and scientists seeking to understand these diseases," adds study co-author Jeffrey Whitsett, M.D., of the Cincinnati Children's Hospital Medical Center. "As the causes of inherited disorders are increasingly understood, we all hope the knowledge gained from these studies will provide insights that will improve the lives of our patients and their families."

Previous studies conducted by Nogee and colleagues identified genetic mutations of both the surfactant protein C gene (SP-C), which results in a defective protein that researchers believe has a toxic effect on the lung metabolism of infants that can eventually lead to scarring of the lungs, and of the surfactant protein B gene (SP-B), which also results in severe surfactant delivery in newborns.

Sergey Shulenin of the NCI's Laboratory of Genomic Diversity was the lead author on the current study. Tarmo Annilo of the NCI's Laboratory of Genomic Diversity and Susan Wert of the Cincinnati Children's Hospital Medical Center also contributed to the study.

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