Faculty Collaboration Database

Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency. J Clin Invest 2018 Jul 02;128(7):3071-3087

Date

06/12/2018

Pubmed ID

29889099

Pubmed Central ID

PMC6026000

DOI

10.1172/JCI98164

Scopus ID

2-s2.0-85049870244 (requires institutional sign-in at Scopus site)   114 Citations

Abstract

Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterized by innate and adaptive immune defects, including low numbers of B cells, neutrophils, eosinophils, and myeloid dendritic cells, as well as T cell and monocyte dysfunctions. Notably, most T cells exhibited a naive phenotype and were unable to evolve into effector memory cells. Functional studies indicated these mutations act as dominant negative. This defect expands the clinical spectrum of human IKZF1-associated diseases from somatic to germline, from haploinsufficient to dominant negative.

Author List

Boutboul D, Kuehn HS, Van de Wyngaert Z, Niemela JE, Callebaut I, Stoddard J, Lenoir C, Barlogis V, Farnarier C, Vely F, Yoshida N, Kojima S, Kanegane H, Hoshino A, Hauck F, Lhermitte L, Asnafi V, Roehrs P, Chen S, Verbsky JW, Calvo KR, Husami A, Zhang K, Roberts J, Amrol D, Sleaseman J, Hsu AP, Holland SM, Marsh R, Fischer A, Fleisher TA, Picard C, Latour S, Rosenzweig SD

Author

James Verbsky MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Amino Acid Sequence
Amino Acid Substitution
B-Lymphocytes
Child
Child, Preschool
Female
Genes, Dominant
Germ-Line Mutation
Heterozygote
Humans
Ikaros Transcription Factor
Immunologic Deficiency Syndromes
Infant
Loss of Function Mutation
Male
Myeloid Cells
Pedigree
Phenotype
Protein Domains
Sequence Homology, Amino Acid
T-Lymphocytes
Young Adult