Surfactant Metabolism Dysfunction, Pulmonary, 5

A number sign (#) is used with this entry because of evidence that pulmonary surfactant metabolism dysfunction-5 (SMDP5) is caused by homozygous mutation in the CSF2RB gene (138981) on chromosome 22q12.

Description

Pulmonary surfactant metabolism dysfunction-5 (SMDP5) is an autosomal recessive lung disorder manifest clinically and pathologically as pulmonary alveolar proteinosis (PAP). PAP is a rare lung disease characterized by the ineffective clearance of surfactant by alveolar macrophages. This results in the accumulation of surfactant-derived lipoproteinaceous material in the alveoli and terminal bronchioles, causing respiratory failure (summary by Greenhill and Kotton, 2009).

For a general phenotypic description and a discussion of genetic heterogeneity of pulmonary surfactant metabolism dysfunction, see SMDP1 (265120).

Clinical Features

Dirksen et al. (1997) described an expression defect of the CSF2RB gene in 4 of 7 pediatric patients with pulmonary alveolar proteinosis. Three patients were diagnosed as neonates, and 1 at age 1 month, after presenting with severe respiratory distress. All were ventilation-dependent. Patient cells failed to express normal levels of beta-c, as shown by flow cytometry, and reduced or absent function of beta-c was demonstrated by ligand binding studies and progenitor clonogenic assays. However, molecular analysis of the CSF2RB gene failed to identify pathogenic mutations.

Tanaka et al. (2011) reported a Japanese woman, born of consanguineous parents, who developed gradual dyspnea on exertion beginning at age 36 years. Chest radiographs showed diffuse homogeneous ground-glass opacities and paving appearance, and lung biopsy showed accumulation of amorphous eosinophilic material in the alveolar space, consistent with a diagnosis of pulmonary alveolar proteinosis. GMCSF (CSF2; 138960) was very high in serum and bronchoalveolar lavage, but autoantibodies to GMCSF were not found. In vitro studies showed that the patient's monocytes failed to differentiate into macrophages after stimulation with GMCSF. There was also a lack of STAT5 (601511) phosphorylation in response to GMCSF or IL3 (147740) stimulation, suggesting defective signaling by the common beta subunit of the GMCSF receptor (CSF2RB). Flow cytometry of patient monocytes showed lack of CSF2RB expression, and CSF2RB mRNA was not detected in patient cells. Neither parent was affected.

Suzuki et al. (2011) reported a 17-year-old girl with PAP. She initially presented at age 9 years with pneumonia, followed 3 months later by progressive dyspnea. The diagnosis was suggested by imaging and bronchoalveolar cytology and confirmed by lung biopsy, which showed periodic acid-Schiff (PAS)-positive material filling alveoli and also present in terminal airways. Serum GMCSF was also increased.

Inheritance

The transmission pattern of SMDP5 in the family reported by Suzuki et al. (2011) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a Japanese woman with late-onset hereditary pulmonary alveolar proteinosis, Tanaka et al. (2011) identified a homozygous truncating mutation in the CSF2RB gene (138981.0001). The unaffected parents were heterozygous for the mutation. Tanaka et al. (2011) speculated that the late onset in this patient may have been due to compensatory factors such as increased serum GMCSF acting through an intact CSF2RA subunit (306250) or increased levels of other inflammatory cells.

In a girl with onset of pulmonary alveolar proteinosis at age 9 years, Suzuki et al. (2011) identified a homozygous missense mutation in the CSF2RB gene (S271L; 138981.0002). In vitro functional expression studies in patient cells showed that the mutation impaired STAT5 phosphorylation following stimulation by GMCSF and IL3. In HEK293 cells transfected with the mutation, increased concentrations of GMCSF demonstrated partial functioning of the mutant receptor, suggesting that GMCSF therapy may be of clinical benefit.

Animal Model

Using Csf2rb-null mice, which develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (HPAP) in children with CSF2RA or CSF2RB mutations, Suzuki et al. (2014) showed that pulmonary macrophage transplantation (PMT) of either wildtype or Csf2rb gene-corrected macrophages without myeloablation was safe and well tolerated. One administration corrected lung disease and secondary systemic manifestations, normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least 1 year, as did therapeutic effects. Suzuki et al. (2014) concluded that their findings identified mechanisms regulating alveolar macrophage population size in health and disease, indicated that GMCSF is required for phenotypic determination of alveolar macrophages, and supported translation of PMT as the first specific therapy for children with hereditary pulmonary alveolar proteinosis.