Background Disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signalling causes pulmonary alveolar proteinosis (PAP). Rarely, genetic defects in neonatal or infant-onset PAP have been identified in CSF2RA. However, no report has clearly identified any function-associated genetic defect in CSF2RB.
Methods and results The patient was diagnosed with PAP at the age of 36 and developed respiratory failure. She was negative for GM-CSF autoantibody and had no underlying disease. Signalling and genetic defects in GM-CSF receptor were screened. GM-CSF-stimulated STAT5 phosphorylation was not observed and GM-CSF-Rβc expression was defective in the patient's blood cells. Genetic screening revealed a homozygous, single-base deletion at nt 631 in exon 6 of CSF2RB on chromosome 22, which caused reductions in GM-CSF dependent signalling and function. Both parents, who were second cousins, showed no pulmonary symptoms, and had normal GM-CSF-signalling, but had a CSF2RB allele with the identical deletion, indicating that the mutant allele may give rise to PAP in an autosomal recessive manner.
Conclusions This is the first report identifying a genetic defect in CSF2RB that causes deficiency of GM-CSF-Rβc expression and impaired signalling downstream. These results suggested that GM-CSF signalling was compensated by other signalling pathways, leading to adult-onset PAP.
- pulmonary alveolar proteinosis
- GM-CSF receptor
- respiratory medicine
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T T and N M contributed equally to this article.
Funding This work was supported in part by grants from the Japanese Ministry of Education and Science, the Ministry of Health, Labor and Welfare of Japan (H15-trans-014), and the Japanese Society for the Promotion of Science (200390230, 20659130).
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the institutional review boards of Nagasaki University and Niigata University.
Provenance and peer review Not commissioned; externally peer reviewed.