. The applicants have recently defined a new clinical syndrome of lethal, inherited surfactant protein deficiency among full term infants. Surfactant protein B deficiency is the best characterized cause of this syndrome. The applicants estimated that between 1 and 30 infants are affected in the annual birth cohort of Missouri (approx. 70,000 births). Gene replacement therapy and lung transplantation are treatment options for surfactant protein B deficiency and possibly for other causes of this syndrome. To evaluate the clinical usefulness of this treatments, genotype-phenotype correlations and reliable estimates of disease frequency are necessary. Using clinical characteristics observed in 33 infants from 20 unrelated families with surfactant protein B deficiency, the applicants will screen linked birth-death certificate data for approx. 1,000,000 live births in Missouri. Relevant identifiers in linked birth-death certificate files will permit chart abstraction and analysis by immunohistology and in-situ hybridization of lung samples from autopsy or lung biopsy for surfactant proteins A, B, and C. Amplified DNA from infants deficient in one or more of these proteins will be prepared from autopsy or lung biopsy tissues by PCR. In affected infants, known mutations will be identified by restriction enzyme digestion, and new mutations or polymorphism will be identified using SSCP analysis or denaturing gel electrophoresis analysis. To determine whether new mutation represent benign polymorphism or pathologic mutations and to estimate the gene frequencies and racial distributions of known and novel mutations, the frequency of each mutation will be assessed in an unbiased population of infants with birth weights greater than 2,000 grams by screening DNA from blood samples anonymous except for race and birth weight obtained for newborn metabolic screening. These studies are critical for rational development of detection, prevention, and treatment strategies, including gene replacement therapy and lung transplantation.
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