One hundred thirty-four germ line PU.1 variants and the agammaglobulinemic patients carrying them

• Published in: Blood Vol. 145; no. 22; pp. 2549 - 2560
• Main Authors: Knox, Ainsley V. C., Cominsky, Lauren Y., Sun, Di, Cruz Cabrera, Emylette, Nolan, Brian E., Ofray, Edann, Benetti, Elisa, Visconti, Camilla, Barzaghi, Federica, Rosenzweig, Sergio D., Lawrence, Monica G., Sullivan, Kathleen E., Yoon, Samuel, Rachimi, Suzanna, Padem, Nurcicek, Conboy, Erin, Stojanovic, Maja, Petrovic, Gordana, Pasic, Srdjan, Church, Joseph, Ferdman, Ronald M., Candotti, Fabio, Arlabosse, Tiphaine, Theodoropoulou, Katerina, Dutmer, Cullen M., Maródi, László, Szücs, Gabriella, Broides, Arnon, Nahum, Amit, Levy, Jacov, Kettunen, Kaisa, Daddali, Ravindra, Seppänen, Mikko, Vänttinen, Markku, Martelius, Timi, Grönholm, Juha, Peri, Matilde, Azzari, Chiara, Ricci, Silvia, Ojaimi, Samar, Edwards, Emily S. J., van Zelm, Menno C., Sun, Jinqiao, Abolhassani, Hassan, Pan-Hammarström, Qiang, Hakonarson, Hakon, Mayr, Daniel, Boztug, Kaan, Boisson, Bertrand, Casanova, Jean-Laurent, Le Coz, Carole, Poon, Gregory M. K., Romberg, Neil
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.05.2025; American Society of Hematology
• Subjects: Adolescent; Adult; Agammaglobulinemia - genetics; Agammaglobulinemia - pathology; Child; Child, Preschool; Female; Germ-Line Mutation; Humans; Infant; Life Sciences; Loss of Function Mutation; Male; Middle Aged; Penetrance; Proto-Oncogene Proteins - genetics; Trans-Activators - genetics; Young Adult
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2024026683

•PU.1 haploinsufficiency causes agammaglobulinemia and dendritic-cell deficiencies with incomplete penetrance and variable expressivity.•Patients with PU.1-mutated agammaglobulinemia experience a broad array of infectious and noninfectious complications, but not leukemia. [Display omitted] Leukopoiesis is lethally arrested in mice lacking the master transcriptional regulator PU.1. Depending on the animal model, subtotal PU.1 loss either induces acute myeloid leukemia or arrests early B-cell and dendritic-cell development. Although humans with absolute PU.1 deficiency have not been reported, a small cadre of congenital agammaglobulinemia patients with sporadic, inborn PU.1 haploinsufficiency was recently described. To better estimate the penetrance, clinical complications, immunophenotypic features, and malignancy risks of PU.1-mutated agammaglobulinemia (PU.MA), a collection of 134 novel or rare PU.1 variants from publicly available databases, institutional cohorts, previously published reports, and unsolved agammaglobulinemia cases were functionally analyzed. In total, 25 loss-of-function (LOF) variants were identified in 33 heterozygous carriers from 21 kindreds across 13 nations. Of individuals harboring LOF PU.1 variants, 22 were agammaglobulinemic, 5 displayed antibody deficiencies, and 6 were unaffected, indicating an estimated disease penetrance of 81.8% with variable expressivity. In a cluster of patients, disease onset was delayed, sometimes into adulthood. All LOF variants conveyed effects via haploinsufficiency, either by destabilizing PU.1, impeding nuclear localization, or directly interfering with transcription. PU.MA patient immunophenotypes consistently demonstrated B-cell, conventional dendritic-cell, and plasmacytoid dendritic-cell deficiencies. Associated infectious and noninfectious symptoms hewed closely to X-linked agammaglobulinemia and not monogenic dendritic-cell deficiencies. No carriers of LOF PU.1 variants experienced hematologic malignancies. Collectively, in vitro and clinical data indicate heterozygous LOF PU.1 variants undermine humoral immunity but do not convey strong leukemic risks. Inborn errors of immunity can reveal nonredundant molecular requirements for the generation, maintenance, and function of human immune cells. In this Plenary Paper, Knox and colleagues report on a large functional complement of 134 variants in SPI1, the gene encoding the transcription factor PU.1, present in molecularly undiagnosed patients with agammaglobulinemia. The authors found 25 variants causing haploinsufficiency in 21 kindreds, each clinically manifested as severe B- and dendritic-cell deficiency with propensity for sinopulmonary bacterial infections. These data greatly expand our knowledge of the recently discovered PU.1-mutated agammaglobulinemia syndrome and provide a reminder that in silico prediction of novel variant pathogenicity is insufficient without functional studies.