Respiratory disease remains a significant cause of morbidity and mortality for newborn infants despite many recent advances in therapy. An inability to produce pulmonary surfactant protein B (SP-B), a hydrophobic, lung specific protein, is a recently recognized cause of fatal neonatal respiratory disease. This proposal tests the hypotheses that 1) SP-B gene mutations are a significant cause of neonatal respiratory disease unresponsive to current therapies, and 2) The nature of the mutations (SP- B genotype) will correlate with the clinical and biochemical features of the illness (phenotype), with mutations leading to absent SP-B expression causing more severe respiratory disease and different secondary alterations in surfactant metabolism than those mutations leading to reduced expression, or altered functional domains of the proSP-B or mature SP-B molecule. SP-B deficient infants will be identified retrospectively by immunohistochemical analysis of autopsy tissue from infants who died from intractable neonatal respiratory failure, and prospectively by analysis of genomic DNA for SP-B gene mutations from infants with clinical signs and symptoms of SP-B deficiency. Genomic DNA from SP-B deficient infants will be analyzed first for known SP-B gene mutations, and novel mutations will be characterized by direct sequencing of genomic DNA. PCR amplified DNA from blood spots obtained from a neonatal screening program will be analyzed for mutations responsible for a SP-B deficiency found in more than one kindred. The estimate of the carrier frequency for SP-B gene mutations in this unselected population will be used to determine the incidence of disease. Finally, SP-B gene mutations will also be looked for in older infants and children with chronic respiratory disease with clinical and pathological features similar to those observed in SP-B deficient children. These studies will provide important data on the incidence of SP-B deficiency and the spectrum of illness associated with abnormalities of SP-B. Understanding the correlation between specific mutations and both clinical and pathologic signs and secondary alterations in surfactant metabolism will provide insights into the role of this essential protein in lung cell metabolism.
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