Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common beta chain expression.
Pulmonary alveolar proteinosis (PAP) is a heterogeneous disorder of genetic or acquired etiologies. In some cases congenital PAP is associated with hereditary surfactant protein (SP)-B deficiency. To date, the molecular defect in the majority of patients with PAP has not been identified. In mice, PAP has been generated by targeted deletion of the genes for either the GM-CSF/IL-3/IL-5 receptor common beta chain (beta c) or GM-CSF. Here, we describe an expression defect of beta c in three of seven pediatric patients with PAP and in one patient with severe lung disease suspected to be PAP. The patients failed to express normal levels of beta c as shown by flow cytometry. Strikingly reduced or absent function of beta c was demonstrated by ligand binding studies and progenitor clonogenic assays. Analysis of beta c DNA revealed a point mutation from proline to threonine at codon 602 in one patient. Our findings provide evidence that a defect in the expression of a hematopoietic cytokine receptor is associated with human PAP.
Dirksen
U
U
Department of Pediatrics, Children's Hospital Medical Center, Heinrich Heine University, Düsseldorf, Germany.
Nishinakamura
R
R
Groneck
P
P
Hattenhorst
U
U
Nogee
L
L
Murray
R
R
Burdach
S
S
D000328:Adult; D019943:Amino Acid Substitution; D002675:Child, Preschool; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006410:Hematopoiesis; D006801:Humans; D007223:Infant; D007700:Kinetics; D017354:Point Mutation; D011510:Proteolipids / Q000378:metabolism; D011649:Pulmonary Alveolar Proteinosis / Q000378:metabolism*; D011663:Pulmonary Surfactants / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency*; D018123:Receptors, Interleukin / Q000172:deficiency*; D016185:Receptors, Interleukin-3 / Q000172:deficiency*; D053649:Receptors, Interleukin-5
D011510:Proteolipids; D011663:Pulmonary Surfactants; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D018123:Receptors, Interleukin; D016185:Receptors, Interleukin-3; D053649:Receptors, Interleukin-5; D016178:Granulocyte-Macrophage Colony-Stimulating Factor