A heterozygous USB1 variant linked to immunodeficiency.

Area of Science:

• Genetics
• Molecular Biology
• Immunology

Background:

• Poikiloderma with neutropenia is a genetic disorder with diverse clinical manifestations.
• The USB1 gene encodes a phosphodiesterase crucial for RNA processing and stability.

Purpose of the Study:

• To investigate the impact of a novel heterozygous de novo USB1 variant (p.P44L) in a patient with neutropenia and hypogammaglobulinemia.
• To elucidate the functional consequences of the p.P44L variant on USB1 protein activity and cellular processes.

Main Methods:

• Identification of a de novo USB1 variant (p.P44L) in a patient.
• In vitro functional assays to assess U6 RNA processing, protein interactions, and subcellular localization.
• Assessment of neutrophil differentiation and clonal capacity.
• Zebrafish model for in vivo analysis of neutrophil and pigmentation defects.

Main Results:

• The p.P44L variant, affecting a conserved N-terminal proline, did not impair U6 RNA processing but altered protein interactions and reduced nuclear localization.
• In vitro, the variant did not inhibit neutrophil differentiation but decreased clonal capacity.
• Zebrafish studies showed reduced neutrophils and pigmentation.

Conclusions:

• The p.P44L variant expands the known spectrum of USB1-associated genetic disorders.
• Heterozygous variants in the N-terminal domain of USB1 can significantly impact clinical phenotypes, including immune dysfunction.
• Hypogammaglobulinemia may be a clinical feature associated with USB1 dysfunction.