A heterozygous USB1 variant linked to immunodeficiency

TL;DR

A new USB1 gene variant is linked to immune issues and low neutrophil counts, expanding understanding of related diseases.

Contribution

A novel heterozygous USB1 variant (p.P44L) is identified and shown to affect immune cell function and pigmentation.

Findings

The p.P44L variant alters USB1 protein localization and interactions but does not disrupt U6 RNA processing.

Zebrafish models show reduced neutrophil counts and pigmentation with the variant.

Hypogammaglobulinemia may be associated with USB1 dysfunction.

Abstract

This study identifies a novel heterozygous USB1 variant (p.P44L) in a patient with hypogammaglobulinemia and low neutrophil counts, showing altered protein localization and function. Functional assays and zebrafish models reveal its impact on immune cells and pigmentation, expanding USB1-related disease understanding.

Poikiloderma with neutropenia is a genetic disorder characterized by skin abnormalities, nail dystrophy, bone anomalies, and neutropenia. USB1 encodes a phosphodiesterase essential for processing spliceosomal U6 RNA and some microRNAs, regulating their stability. This study describes a heterozygous de novo USB1 variant (p.P44L) identified in a patient with recurrent infections, hypogammaglobulinemia, and low neutrophil counts. Unlike previously reported mutations, p.P44L affects a conserved proline in the N-terminal domain, predicted to be critical for protein interactions and stability. Functional assays revealed that while U6 RNA processing remained intact, the variant altered protein interactions and subcellular localization, reducing nuclear presence and accumulation within nuclear speckles. In vitro, the variant did not prevent neutrophil differentiation but reduced clonal capacity. In zebrafish, it led to reduced neutrophils and pigmentation. These findings expand the spectrum of genetic traits associated with USB1 and suggest that a heterozygous variant affecting the N-terminal domain of USB1 impacts clinical phenotypes and that hypogammaglobulinemia may be associated with USB1 dysfunction.

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