Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB

J Med Genet. 2011 Mar;48(3):205-9. doi: 10.1136/jmg.2010.082586. Epub 2010 Nov 12.

Abstract

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Chromosome Deletion*
  • Chromosomes, Human, Pair 22
  • Exons
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Humans
  • Pulmonary Alveolar Proteinosis / genetics*
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics*
  • Respiratory Insufficiency / etiology
  • Respiratory Insufficiency / genetics
  • Signal Transduction

Substances

  • CSF2RA protein, human
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor