Compound SFTPB 1549C-->GAA (121ins2) and 457delC heterozygosity in severe congenital lung disease and surfactant protein B (SP-B) deficiency.

Several human respiratory disorders have been linked to an abnormality of pulmonary surfactant synthesis or turnover. Among those conditions, hereditary deficiency in the hydrophobic surfactant protein B (SP-B) has been recognized as a rare cause of respiratory failure in term newborn infants. Homozygosity for a common mutation (1549C-->GAA, or 121ins2) of the SP-B-encoding gene (SFTPB) results in rapidly fatal respiratory failure, with complete absence of the mRNA and protein observed in lung fluid or biopsy specimens. Hereditary SP-B deficiency is also associated with aberrant processing of proSP-C and deficiency of the active SP-C peptide. In the present study, we characterized the SFTPB gene in an infant with severe unexplained respiratory distress and identified a paternally derived 1549C-->GAA lesion, as well as a hitherto unreported mutation (457delC) inherited from the mother. Analysis of bronchoalveolar lavage fluid demonstrated the complete absence of SP-B. However, unlike previous infants with hereditary SP-B deficiency, proSP-C was processed to the active SP-C peptide, suggesting that the defect in SP-B, rather than SP-C, caused the respiratory distress in this infant. The present findings demonstrate the importance of SFTPB in pulmonary function and support the need for further genotype-phenotype correlations in patients with SP-B deficiency.