title: Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB.
abstract: BACKGROUND
  Disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signalling causes pulmonary alveolar proteinosis (PAP). Rarely, genetic defects in neonatal or infant-onset PAP have been identified in CSF2RA. However, no report has clearly identified any function-associated genetic defect in CSF2RB.
  
  
  RESULTS
  The patient was diagnosed with PAP at the age of 36 and developed respiratory failure. She was negative for GM-CSF autoantibody and had no underlying disease. Signalling and genetic defects in GM-CSF receptor were screened. GM-CSF-stimulated STAT5 phosphorylation was not observed and GM-CSF-Rβc expression was defective in the patient's blood cells. Genetic screening revealed a homozygous, single-base deletion at nt 631 in exon 6 of CSF2RB on chromosome 22, which caused reductions in GM-CSF dependent signalling and function. Both parents, who were second cousins, showed no pulmonary symptoms, and had normal GM-CSF-signalling, but had a CSF2RB allele with the identical deletion, indicating that the mutant allele may give rise to PAP in an autosomal recessive manner.
  
  
  CONCLUSIONS
  This is the first report identifying a genetic defect in CSF2RB that causes deficiency of GM-CSF-Rβc expression and impaired signalling downstream. These results suggested that GM-CSF signalling was compensated by other signalling pathways, leading to adult-onset PAP.
authors.affiliation: Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Natsuki
authors.initials: N
authors.lastname: Motoi
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Tsuchihashi
authors.forename: Ryushi
authors.initials: R
authors.lastname: Tazawa
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Kaneko
authors.forename: Takahito
authors.initials: T
authors.lastname: Nei
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Tomayoshi
authors.initials: T
authors.lastname: Hayashi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tagawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagayasu
authors.forename: Futoshi
authors.initials: F
authors.lastname: Kuribayashi
authors.forename: Koya
authors.initials: K
authors.lastname: Ariyoshi
authors.forename: Koh
authors.initials: K
authors.lastname: Nakata
authors.forename: Konosuke
authors.initials: K
authors.lastname: Morimoto
mesh_terms: D000328:Adult; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22; D005091:Exons; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D011649:Pulmonary Alveolar Proteinosis / Q000235:genetics*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D012131:Respiratory Insufficiency / Q000209:etiology / Q000235:genetics; D015398:Signal Transduction
chemical_list: C521678:CSF2RA protein, human; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor