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¹ Division of Pulmonary Biology, ² Division of Pulmonary Medicine, ³ Division of Human Genetics, and ⁴ Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
⁵ Departments of Pediatrics and Biomedical Engineering, Wake Forest University School of Medicine, Winston-Salem, NC 27157
⁶ Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21205
⁷ Department of Pathology, Texas Children's Hospital, Houston, TX 77030
⁸ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267

CORRESPONDENCE Bruce C. Trapnell: Bruce.Trapnell{at}cchmc.org

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-R) 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-R–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-R, 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.

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