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. METHODS AND 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.
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. METHODS AND 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: Timothy R Hercus; Winnie L T Kan; Sophie E Broughton; Denis Tvorogov; Hayley S Ramshaw; Jarrod J Sandow; Tracy L Nero; Urmi Dhagat; Emma J Thompson; Karen S Cheung Tung Shing; Duncan R McKenzie; Nicholas J Wilson; Catherine M Owczarek; Gino Vairo; Andrew D Nash; Vinay Tergaonkar; Timothy Hughes; Paul G Ekert; Michael S Samuel; Claudine S Bonder; Michele A Grimbaldeston; Michael W Parker; Angel F Lopez Journal: Cold Spring Harb Perspect Biol Date: 2018-06-01 Impact factor: 10.005
Authors: Jamie Campbell; Josquin Nys; Laura Eghobamien; E Suzanne Cohen; Matthew J Robinson; Matthew A Sleeman Journal: MAbs Date: 2016-08-12 Impact factor: 5.857
Authors: De S Shang; Yi M Yang; Hu Zhang; Li Tian; Jiu S Jiang; Yan B Dong; Ke Zhang; Bo Li; Wei D Zhao; Wen G Fang; Yu H Chen Journal: J Cereb Blood Flow Metab Date: 2016-07-21 Impact factor: 6.200