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Defective monocyte plasticity and altered cAMP pathway characterize USB1-mutated poikiloderma with neutropenia
Prahlad Parajuli1,2, Douglas B Craig2,3, Manisha Gadgeel4,5
1Department of Pharmaceutical and Health Sciences, Eugene Applebaum College of Pharmacy, Wayne State University, Detroit, Michigan, USA.
Abstract:
Poikiloderma with neutropenia (PN) Clericuzio type (OMIM #604173) is a rare disease with areas of skin hyper- and hypopigmentation caused by biallelic USB1 variants. The current study was spurred by poor healing of a perianal tear wound in one affected child homozygous for c.266-1G>A (p.E90Sfster8) mutation, from a family reported previously. Treatment with G-CSF/CSF3 or GM-CSF/CSF2 transiently increased neutrophil/monocytes count with no effect on wound healing. Analysis of peripheral blood revealed a lack of non-classical (CD14+/- CD16+ ) monocytes, associated with a systemic inflammatory cytokine profile, in the two affected brothers. Importantly, despite normal expression of cognate receptors, monocytes from PN patients did not respond to M-CSF or IL-34 in vitro, as determined by cytokine secretion or CD16 expression. RNAseq of monocytes showed 293 differentially expressed genes, including significant downregulation of GATA2, AKAP6 and PDE4DIP that are associated with leucocyte differentiation and cyclic adenosine monophosphate (cAMP) signalling. Notably, the plasma cAMP was significantly low in the PN patients. Our study revealed a novel association of PN with a lack of non-classical monocyte population. The defects in monocyte plasticity may contribute to disease manifestations in PN and a defective cAMP signalling may be the primary effect of the splicing errors caused by USB1 mutation.
Insights
Poikiloderma with neutropenia (PN) patients lack a specific monocyte population, impacting immune cell function. This study links USB1 mutations to defective cyclic adenosine monophosphate (cAMP) signaling and monocyte plasticity issues in PN.
Area of Science:
- Genetics and Immunology
- Rare Diseases Research
Background:
- Poikiloderma with neutropenia (PN) Clericuzio type is a rare genetic disorder characterized by skin pigmentation changes and neutropenia, caused by biallelic USB1 variants.
- Previous treatments with G-CSF/CSF3 or GM-CSF/CSF2 showed transient effects on blood cell counts but did not improve wound healing in affected individuals.
Purpose of the Study:
- To investigate the underlying mechanisms of poor wound healing and immune dysregulation in PN patients with USB1 mutations.
- To identify novel cellular and molecular defects associated with PN.
Main Methods:
- Analysis of peripheral blood monocytes from PN patients.
- In vitro functional assays of patient-derived monocytes stimulated with M-CSF and IL-34.
- RNA sequencing (RNAseq) of monocytes to identify differentially expressed genes.
- Measurement of plasma cyclic adenosine monophosphate (cAMP) levels.
Main Results:
- PN patients exhibited a lack of non-classical monocytes (CD14+/- CD16+) and a systemic inflammatory cytokine profile.
- Patient monocytes showed impaired responses to M-CSF and IL-34, despite normal receptor expression.
- RNAseq revealed downregulation of genes involved in leukocyte differentiation and cAMP signaling, including GATA2, AKAP6, and PDE4DIP.
- Significantly reduced plasma cAMP levels were observed in PN patients.
Conclusions:
- This study identifies a novel association between PN and the absence of non-classical monocytes.
- Defects in monocyte plasticity and cAMP signaling, stemming from USB1 mutations, likely contribute to the clinical manifestations of PN.
