DNA sequence changes in the gene encoding the GM-CSF / IL-3 / IL-5 receptor common β chain in infants with pulmonary alveolar proteinosis

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. Genomic DNA from 3 patients with PAP and reduced βc expression was analyzed by PCR amplification of the βc gene and direct sequencing of coding exons and flanking intron sequence. 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 592 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 Gly592Val change in 2 of 120 chromosomes (1.6%) from control subjects without lung disease, and the Pro603Thr change has been previously shown in healthy controls, indicating that these changes are likely polymorphisms. The other sequence changes were C->T transitions at codons 234, 426, and 648 that did not result in amino acid substitutions. None of the sequence deviations occurred near splice junctions or at points of known structural or functional significance. We conclude that the reduced βc expression in these 3 infants was not due to mutations in the coding regions of their βc genes and that the mechanism for their decreased βc expression remains undetermined. Mutations within either noncoding sequences in the βc gene or in genes encoding trans acting factors could be responsible for the observed reduction in βc expression. Alternatively, the proximate cause of lung disease in these children may be unrelated to reduced βc expression.