Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA

J Exp Med. 2008 Nov 24;205(12):2703-10. doi: 10.1084/jem.20080990. Epub 2008 Oct 27.

Abstract

Primary pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of surfactant in the lungs that is presumed to be mediated by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling based on studies in genetically modified mice. The effects of GM-CSF are mediated by heterologous receptors composed of GM-CSF binding (GM-CSF-Ralpha) and nonbinding affinity-enhancing (GM-CSF-Rbeta) subunits. We describe PAP, failure to thrive, and increased GM-CSF levels in two sisters aged 6 and 8 yr with abnormalities of both GM-CSF-Ralpha-encoding alleles (CSF2RA). One was a 1.6-Mb deletion in the pseudoautosomal region of one maternal X chromosome encompassing CSF2RA. The other, a point mutation in the paternal X chromosome allele encoding a G174R substitution, altered an N-linked glycosylation site within the cytokine binding domain and glycosylation of GM-CSF-Ralpha, severely reducing GM-CSF binding, receptor signaling, and GM-CSF-dependent functions in primary myeloid cells. Transfection of cloned cDNAs faithfully reproduced the signaling defect at physiological GM-CSF concentrations. Interestingly, at high GM-CSF concentrations similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow progression of disease in these children. These results establish that GM-CSF signaling is critical for surfactant homeostasis in humans and demonstrate that mutations in CSF2RA cause familial PAP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Child
  • Chromosomes, Human, X
  • DNA Mutational Analysis
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Homeostasis
  • Humans
  • Male
  • Mice
  • Molecular Sequence Data
  • Mutation*
  • Pulmonary Alveolar Proteinosis / genetics*
  • Pulmonary Alveolar Proteinosis / physiopathology
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics*
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Signal Transduction / physiology

Substances

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

Associated data

  • GENBANK/BC070085