One hundred thirty-four germ line PU.1 variants and the agammaglobulinemic patients carrying them
Abstract
Abstract 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.
Article Details
Authors (53)
Ainsley V. C. Knox
1Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA
Lauren Y. Cominsky
1Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA
Di Sun
School of Chemistry and Chemical Engineering, State Key Laboratory of Crystal Materials
Emylette Cruz Cabrera
1Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA
Brian E. Nolan
3Division of Rheumatology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL
Edann Ofray
1Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA
Elisa Benetti
5Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
Camilla Visconti
7Vita-Salute San Raffaele University, Milan, Italy
Federica Barzaghi
San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan
Sergio D. Rosenzweig
Department of Laboratory Medicine, NIH Clinical Center, Bethesda, MD
Monica G. Lawrence
10Division of Asthma, Allergy and Immunology, Department of Medicine, University of Virginia, Charlottesville, VA
Kathleen E. Sullivan
1Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA
Samuel Yoon
1Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA
Suzanna Rachimi
1Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA
Nurcicek Padem
13Division of Pediatric Pulmonology, Allergy-Immunology, and Sleep Medicine, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
Erin Conboy
Maja Stojanovic
Gordana Petrovic
17Department of Immunology, Mother and Child Health Care Institute of Serbia, Belgrade, Serbia
Srdjan Pasic
16Department of Medicine, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
Joseph Church
18Division of Clinical Immunology and Allergy, Children’s Hospital Los Angeles, Los Angeles, CA
Ronald M. Ferdman
18Division of Clinical Immunology and Allergy, Children’s Hospital Los Angeles, Los Angeles, CA
Fabio Candotti
Tiphaine Arlabosse
21Department of Woman, Mother, Child, Unit of Pediatric Immunology, Allergology and Rheumatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Katerina Theodoropoulou
21Department of Woman, Mother, Child, Unit of Pediatric Immunology, Allergology and Rheumatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Cullen M. Dutmer
22Department of Pediatrics, Section of Allergy and Immunology, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO
László Maródi
Gabriella Szücs
24Department of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Arnon Broides
25Pediatric Immunology Clinic, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Amit Nahum
Jacov Levy
25Pediatric Immunology Clinic, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Kaisa Kettunen
26Laboratory of Genetics, HUS Diagnostic Center, University of Helsinki, Helsinki, Finland
Ravindra Daddali
27Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
Mikko Seppänen
27Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
Markku Vänttinen
29Department of Medicine, Unit of Infectious Diseases and Hospital Hygiene, Kuopio University Hospital, Kuopio, Finland
Timi Martelius
31Inflammation Center, Department of Infectious Disease, HUS Helsinki University Hospital and University of Helsinki, Helsinki, Finland
Juha Grönholm
27Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
Matilde Peri
33Department of Health Sciences, University of Florence, Florence, Italy
Chiara Azzari
33Department of Health Sciences, University of Florence, Florence, Italy
Silvia Ricci
33Department of Health Sciences, University of Florence, Florence, Italy
Samar Ojaimi
35Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC, Australia
Emily S. J. Edwards
37Department of Immunology, School of Translational Medicine, Monash University, Melbourne, VIC, Australia
Menno C. van Zelm
37Department of Immunology, School of Translational Medicine, Monash University, Melbourne, VIC, Australia
Jinqiao Sun
39Department of Clinical Immunology, Children's Hospital of Fudan University, National Children Medical Center, Shanghai, China
Hassan Abolhassani
Qiang Pan-Hammarström
Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institute
Hakon Hakonarson
Daniel Mayr
44Saint Anna Children’s Cancer Research Institute, Vienna, Austria
Kaan Boztug
Bertrand Boisson
Jean-Laurent Casanova
Carole Le Coz
51Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, National Centre for Scientific Research, INSERM, Toulouse, France
Gregory M. K. Poon
52Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA
Neil Romberg