A heterozygous USB1 variant linked to immunodeficiency
Poikiloderma with neutropenia is a genetic disorder characterized by skin abnormalities, nail dystrophy, bone anomalies, and neutropenia. <i>USB1</i> encodes a phosphodiesterase essential for processing spliceosomal U6 RNA and some microRNAs, regulating their stability. This study describes a heterozygous <i>de novo</i> 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. <i>In vitro</i>, 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 <i>USB1</i> 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.
Authors
- Chantal Lagresle‐Peyrou (ORCID: https://orcid.org/0000-0002-2216-6453)
- Mônica Beltrame (ORCID: https://orcid.org/0000-0001-5094-3494)
- Despina Moshous (ORCID: https://orcid.org/0000-0001-6719-3693)
- Sven Kracker (ORCID: https://orcid.org/0000-0003-4543-8236)
- Sara Mercurio (ORCID: https://orcid.org/0000-0003-3469-8323)
- Nicolas Goudin (ORCID: https://orcid.org/0000-0002-3967-4016)
- Mélanie Parisot (ORCID: https://orcid.org/0000-0003-4312-2035)
- Nidia Moreno-Corona (ORCID: https://orcid.org/0000-0001-5248-0454)
- Alice Valagussa (ORCID: https://orcid.org/0009-0001-1809-7803)
- Margot Tragin
Institutions
- Hôpital Necker-Enfants Malades (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- University of Milan (IT)
- Université Paris-Est Créteil (FR)
- Université Paris Cité (FR)
- Centre de Référence Déficits Immunitaires Héréditaires (FR)
- La Ligue Contre le Cancer (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Groupe Hospitalier Cochin - Port-Royal, Hôtel-Dieu, Broca - La Collégiale (FR)
- Structure Fédérative de Recherche en Biologie et Santé de Rennes (FR)
- Institut des Maladies Génétiques Imagine (FR)
- University of Milano-Bicocca (IT)
Publication Details
- Journal
- Journal of Human Immunity
- Published
- 2025-09-19
- DOI
- https://doi.org/10.70962/jhi.20250110
- Primary Topic
- Blood disorders and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Università degli Studi di Milano
- Institut des maladies génétiques Imagine
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique
- Université Claude Bernard Lyon 1
- Etablissement Français du Sang
- European Society for Immunodeficiencies