Abstract 1775 Poster Session IV, Tuesday, 5/4 (poster 345)

Reduced expression of the GM-CSF / IL-3 / IL-5 receptor common β chain (βc) has been associated with the development of pulmonary alveolar proteinosis (PAP) in experimental animals and human infants. In order to test the hypothesis that the reduction in βc expression was the basis for lung disease in these children, we examined the gene encoding the βc for mutations that could account for reduced βc expression or function. We evaluated 3 infants with PAP and reduced βc protein expression. These children had onset of lung disease in the neonatal period. Genomic DNA from these infants was analyzed by PCR amplification of the βc gene and direct sequencing of PCR products. Five deviations from the published gene sequence were identified. One infant was heterozygous for a G→T transversion leading to a conservative amino acid substitution (gly→val) at codon 591 and a previously described C→A transversion leading to an amino acid substitution (pro→thr) at codon 603. However, restriction analysis demonstrated the presence of the Gly591Val change on 2 of 120 chromosomes (1.6%) and the Pro603Thr on 3 of 64 chromosomes (3.1%) examined from control subjects without lung disease, suggesting that these changes are polymorphisms. The other sequence changes were C→T transitions at codons 234, 426, and 648 that did not result in amino acid substitutions. No sequence deviations occurred near or at splice junctions, at points of known structural or functional significance, or in the 5′ untranslated sequences that have been shown to be important for βc expression. We conclude that the reduced βc expression in these 3 infants was not due to mutations within their βc genes and that the mechanism for their decreased βc expression remains undetermined. Mutations within genes encoding trans acting factors could be responsible for the observed reduction in βc expression. Alternatively, the primary cause of lung disease in these children may be unrelated to reduced βc expression.