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.
| Nevel, Rebekah J; Garnett, Errine T; Worrell, John A et al. (2016) Persistent Lung Disease in Adults with NKX2.1 Mutation and Familial Neuroendocrine Cell Hyperplasia of Infancy. Ann Am Thorac Soc 13:1299-304 |
| Thavagnanam, Surendran; Cutz, Ernest; Manson, David et al. (2013) Variable clinical outcome of ABCA3 deficiency in two siblings. Pediatr Pulmonol 48:1035-8 |
| Hamvas, Aaron; Deterding, Robin R; Wert, Susan E et al. (2013) Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest 144:794-804 |
| Henderson, Lindsay B; Melton, Kristin; Wert, Susan et al. (2013) Large ABCA3 and SFTPC deletions resulting in lung disease. Ann Am Thorac Soc 10:602-7 |
| Young, Lisa R; Deutsch, Gail H; Bokulic, Ronald E et al. (2013) A mutation in TTF1/NKX2.1 is associated with familial neuroendocrine cell hyperplasia of infancy. Chest 144:1199-1206 |
| Flamein, Florence; Riffault, Laure; Muselet-Charlier, Céline et al. (2012) Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children. Hum Mol Genet 21:765-75 |
| Agrawal, Amit; Hamvas, Aaron; Cole, F Sessions et al. (2012) An intronic ABCA3 mutation that is responsible for respiratory disease. Pediatr Res 71:633-7 |
| Gower, W Adam; Nogee, Lawrence M (2011) Surfactant dysfunction. Paediatr Respir Rev 12:223-9 |
| Popler, J; Gower, W A; Mogayzel Jr, P J et al. (2010) Familial neuroendocrine cell hyperplasia of infancy. Pediatr Pulmonol 45:749-55 |
| Gower, W Adam; Wert, Susan E; Ginsberg, Jennifer S et al. (2010) Fatal familial lung disease caused by ABCA3 deficiency without identified ABCA3 mutations. J Pediatr 157:62-8 |
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