Novel de novo dominant PSMB10 variants in three patients with immune deficiency and liver disease

Benjamin Fournier; Léa Poirier; Vincent Abramowski; Etienne Merlin; Hélène Deutsch; Paul Bastard; Isabelle Callebaut; Capucine Picard; Jérémie Rosain; Sébastien Küry; Stéphane Bézieau; Monique Fabre; Martin Castelle; Bénédicte Neven; Despina Moshous; Jean-Pierre de Villartay; Frédéric Ebstein

doi:10.70962/jhi.20250096

Novel de novo dominant PSMB10 variants in three patients with immune deficiency and liver disease

J Hum Immun. 2025 Nov 18;2(1):e20250096. doi: 10.70962/jhi.20250096. eCollection 2026 Jan 5.

Authors

Benjamin Fournier^#^{1

2}, Léa Poirier^#³, Vincent Abramowski^{4

5}, Etienne Merlin^{6

7

8}, Hélène Deutsch⁹, Paul Bastard^{1

10

11

12}, Isabelle Callebaut¹³, Capucine Picard^{1

2

14}, Jérémie Rosain^{10

14}, Sébastien Küry³, Stéphane Bézieau^{3

15}, Monique Fabre¹⁶, Martin Castelle¹, Bénédicte Neven^#^{1

17}, Despina Moshous^#^{1

4

5

18}, Jean-Pierre de Villartay^#^{4

5}, Frédéric Ebstein^#³

Affiliations

¹ Paediatric Haematology-Immunology and Rheumatology Unit, Necker Hospital, AP-HP.Centre - Université Paris Cité, Paris, France.
² Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Inserm UMR 1163, Institut Imagine, Paris, France.
³ Nantes Université, CNRS, INSERM, l'institut du Thorax, Nantes, France.
⁴ Université Paris Cité, Imagine Institute, Laboratory "Genome Dynamics in the Immune System," INSERM UMR 1163, Paris, France.
⁵ Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France.
⁶ Department of Pediatrics, Clermont-Ferrand University Hospital, Clermont-Ferrand, France.
⁷ Clermont Auvergne University, INSERM, Clermont-Ferrand, France.
⁸ Clermont Auvergne University, INRA, UMR 1019 UNH, ECREIN, Clermont-Ferrand, France.
⁹ Department of Pediatric Onco-Hematology, University Hospital, Vandoeuvre-les-Nancy, France.
¹⁰ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
¹¹ Paris Cité University, Imagine Institute, Paris, France.
¹² St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
¹³ Sorbonne Université, Muséum National d'Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC, Paris, France.
¹⁴ Study Center for Primary Immunodeficiencies, Necker Hospital, AP-HP.Centre - Université Paris Cité, Paris, France.
¹⁵ Nantes Université, CHU de Nantes, Service de Génétique Médicale, Nantes, France.
¹⁶ Department of Pathology, Necker Hospital, AP-HP.Centre - Université Paris Cité, Paris, France.
¹⁷ Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Université Paris Cité, Imagine Institut, INSERM UMR 1163, Paris, France.
¹⁸ Centre de référence des déficits Immunitaires Héréditaires, Necker Hospital, AP-HP.Centre - Université Paris Cité, Paris, France.

^# Contributed equally.

Abstract

Background and objective: Despite significant advances, the molecular basis and thus patient-tailored therapeutic options for inborn errors of immunity remain unknown in a significant number of patients.

Methods: We investigated three patients from unrelated families with inborn errors of immunity and severe liver disease. Clinical, immunological, and histological (only in one patient for the latter) data were collected, and trio whole exome sequencing was performed.

Results: Whole exome sequencing identified heterozygous de novo variants in PSMB10 (p.Asp205Ala and p.Ser208Phe), a gene encoding a specific subunit of the immuno- and thymoproteasome. Analysis showed poor integration into the proteasome complex of PSMB10 variants, thereby exerting a dominant-negative effect on the PSMB9 subunit.

Conclusion: Dominant PSMB10 variants should be considered in genetic screening for SCID and CID, especially in patients with associated liver disease. Very severe endothelial-like disease before and after HSCT and very poor outcomes after HSCT should weigh up the indication of HSCT.