Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) is a cytokine that plays a key role in the immune/inflammatory cascade. The protein functions as a white blood cell growth factor, stimulating stem cells to produce granulocytes and monocytes. GM-CSF carries out this function by activating signaling pathways via a cell surface receptor known as the Colony Stimulating Factor 2 Receptor. This is a heterodimeric protein made up of a ligand-binding alpha subunit, encoded by the CSF2RA gene, and an affinity enhancing beta subunit, encoded by the CSF2RB gene.
Due to its role in the immune system, mutations in the CSF2RA gene can have strong pathological consequences. The gene has been implicated in Surfactant Metabolism Dysfunction, Pulmonary, 4 (SMDP4), a rare interstitial lung disorder characterized by respiratory distress and surfactant protein exudate accumulation in the alveoli.
The gene is located on the short arm of the X chromosome and spans a length of 56.2 kb of DNA. Its coding sequence is contained within 19 exons and it encodes a 46.2 kDa protein product consisting of 400 amino acids. Several additional isoforms of the CSF2RA protein exist due to alternatively spliced transcript variants. The gene is seen to be overexpressed in peripheral blood mononuclear cells, monocytes and placenta. Gene variants that have been implicated in SMDP4 include a G174R missense mutation, which causes a truncated CSF2RA protein and a large deletion of exons 5 through 13 that results in a complete absence of the protein.
Al-Haidary et al. (2017) described a 5-year-old Saudi boy from a consanguineous family with pulmonary alveolar proteinosis (PAP). He first presented with dyspnea, weight loss and respiratory distress. Investigations revealed ground-glass opacification and interlobular septal thickening in his chest (crazy paving pattern) with milky bronchoalveolar lavage, positive for periodic acid–Schiff stain. His serum GM-CSF levels were high and GM-CSF autoantibodies were negative. He was found to be homozygous for a novel c.533G>A (p.Cys178Tyr) variant in the CSF2RA gene. His parents were both heterozygous while his 3.5-year-old sister was found to be homozygous for the mutation. She was asymptomatic and an examination found no abnormal findings. The patient was diagnosed with congenital PAP due to a CSF2RA gene mutation and responded well to therapeutic whole lung lavage treatment.
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