Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome.
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van der Made Caspar I, Kersten Simone, Chorin Odelia, Engelhardt Karin R, Ramakrishnan Gayatri, Griffin Helen, Schim van der Loeff Ina, Venselaar Hanka, Rothschild Annick Raas, Segev Meirav, Schuurs-Hoeijmakers Janneke H M, Mantere Tuomo, Essers Rick, Esteki Masoud Zamani, Avital Amir L, Loo Peh Sun, Simons Annet, Pfundt Rolph, Warris Adilia, Seyger Marieke M, van de Veerdonk Frank L, Netea Mihai G, Slatter Mary A, Flood Terry, Gennery Andrew R, Simon Amos J, Lev Atar, Frizinsky Shirley, Barel Ortal, van der Burg Mirjam, Somech Raz, Hambleton Sophie, Henriet Stefanie S V, Hoischen Alexander
Аннотация
Mutations in proteasome β-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome β2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash. Remaining T cells had limited T cell receptor repertoires, a skewed memory phenotype, and an elevated CD4/CD8 ratio. Bone marrow examination indicated severely impaired B cell maturation with limited V(D)J recombination. All infants received an allogeneic stem cell transplant and exhibited a variety of severe inflammatory complications thereafter, with 2 peri-transplant and 2 delayed deaths. The single long-term transplant survivor showed evidence for genetic rescue through revertant mosaicism overlapping the affected PSMB10 locus. The identified variants (c.166G>C [p.Asp56His] and c.601G>A/c.601G>C [p.Gly201Arg]) were predicted in silico to profoundly disrupt 20S immunoproteasome structure through impaired β-ring/β-ring interaction. Our identification of PSMB10 mutations as a cause of SCID-Omenn syndrome reinforces the connection between PRAAS-related diseases and SCID.