Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB

作者：Tanaka Takeshi; Motoi Natsuki; Tsuchihashi Yoshiko; Tazawa Ryushi; Kaneko Chinatsu; Nei Takahito; Yamamoto Toshiyuki; Hayashi Tomayoshi; Tagawa Tsutomu; Nagayasu Takeshi; Kuribayashi Futoshi; Ariyoshi Koya; Nakata Koh^*; Morimoto Konosuke

来源：Journal of Medical Genetics, 2011, 48(3): 205-209.

DOI：10.1136/jmg.2010.082586

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-R beta c 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-Rbc expression and impaired signalling downstream. These results suggested that GM-CSF signalling was compensated by other signalling pathways, leading to adult-onset PAP.

• 出版日期2011-3