Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA

Takuji Suzuki, Takuro Sakagami, Bruce K. Rubin, Lawrence M. Nogee, Robert E. Wood, Sarah L. Zimmerman, Teresa Smolarek, Megan K. Dishop, Susan E. Wert, Jeffrey A. Whitsett, Gregory Grabowski, Brenna C. Carey, Carrie Stevens, Johannes C.M. Van Der Loo, Bruce C. Trapnell

Research output: Contribution to journalArticlepeer-review


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-Ra) and nonbinding affinity-enhancing (GM-CSF- Rβ) 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-Rα-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-Rα, 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.

Original languageEnglish (US)
Pages (from-to)2703-2710
Number of pages8
JournalJournal of Experimental Medicine
Issue number12
StatePublished - Nov 12 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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