TY - JOUR
T1 - Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA
AU - Suzuki, Takuji
AU - Sakagami, Takuro
AU - Rubin, Bruce K.
AU - Nogee, Lawrence M.
AU - Wood, Robert E.
AU - Zimmerman, Sarah L.
AU - Smolarek, Teresa
AU - Dishop, Megan K.
AU - Wert, Susan E.
AU - Whitsett, Jeffrey A.
AU - Grabowski, Gregory
AU - Carey, Brenna C.
AU - Stevens, Carrie
AU - Van Der Loo, Johannes C.M.
AU - Trapnell, Bruce C.
PY - 2008/11/12
Y1 - 2008/11/12
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20080990
DO - 10.1084/jem.20080990
M3 - Article
C2 - 18955570
AN - SCOPUS:58149313016
SN - 0022-1007
VL - 205
SP - 2703
EP - 2710
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 12
ER -