Abstract
Backgroung: Surfactant protein B (SP-B) is essential for normal lung function. Differences in SP-B levels may be influenced by variation in the encoding gene (SFTPB). SFTPB SNP Ile131Thr affects proSP-B N-terminal glycosylation.
Aims: To investigate whether proSP-B glycosylation affects propeptide processing and secretion kinetics, and to determine whether differences in amniotic fluid SP-B levels associate with SFTPB polymorphisms.
Methods: CHO cell lines expressing either proSP-B/Ile or proSP-B/Thr were generated. The effect of glycosylation on proSP-B secretion kinetics was investigated by pulse-chase labeling. Sample pairs of amniotic fluid and umbilical cord blood were collected from term pregnancies. SP-B in amniotic fluid was quantitated by Western analysis and immunoblotting. Relative protein levels were assessed to detect correlations with four SFTPB polymorphisms. To study whether there is any preferential transcription between the allelic variants of Ile131Thr, cDNA from heterozygous lung tissue samples was used for allelic expression imbalance assay.
Results: Glycosylated proSP-B/Thr was secreted from CHO cells at a significantly slower rate than proSP-B/Ile (p=0.0012). SP-B levels in amniotic fluid differed significantly among the Ile131Thr genotype groups (p=0.016). This SNP, together with gestational age and respiratory distress, was a significant covariate for SP-B levels in a recessive inheritance model. Expression levels of Ile and Thr variant mRNAs were equal in the heterozygote tissue samples, indicating no allelic expression imbalance.
Conclusion: Our results suggest that Ile131Thr variation-dependent proSP-B glycosylation retards the secretion of SP-B in vitro and in vivo via a post-transcriptional mechanism. Ile131Thr polymorphism may therefore predispose to respiratory distress syndrome.
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Huusko, J., Taponen, S., Petäjä-Repo, U. et al. Allele-Specific Glycosylation of ILE131THR Variant Retards Surfactant Protein B Processing and Secretion: Basis of Predisposition to Respiratory Distress Syndrome. Pediatr Res 70 (Suppl 5), 656 (2011). https://doi.org/10.1038/pr.2011.881
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DOI: https://doi.org/10.1038/pr.2011.881
