A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS

Nat Immunol. 2021 Jul;22(7):893-903. doi: 10.1038/s41590-021-00951-z.

Motoi Yamashita ¹ ², Hye Sun Kuehn ^# ³, Kazuki Okuyama ^# ², Satoshi Okada ⁴, Yuzaburo Inoue ⁵ ⁶, Noriko Mitsuiki ¹, Kohsuke Imai ¹ ⁷, Masatoshi Takagi ¹, Hirokazu Kanegane ¹ ⁸, Masahiro Takeuchi ⁹ ¹⁰, Naoki Shimojo ⁵ ¹¹, Miyuki Tsumura ⁴, Aditya K Padhi ¹², Kam Y J Zhang ¹², Bertrand Boisson ¹³ ¹⁴ ¹⁵, Jean-Laurent Casanova ¹³ ¹⁴ ¹⁵ ¹⁶, Osamu Ohara ¹⁷, Sergio D Rosenzweig ³, Ichiro Taniuchi ¹⁸, Tomohiro Morio ¹⁹

Affiliations

1 Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
2 Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
3 Immunology Service, Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD, USA.
4 Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
5 Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan.
6 Department of Allergy and Rheumatology, Chiba Children's Hospital, Chiba, Japan.
7 Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
8 Department of Child Health and Development, Tokyo Medical and Dental University, Tokyo, Japan.
9 Department of Hematology, Chiba University Hospital, Chiba, Japan.
10 Department of Hematology and Medical Oncology, Chiba Cancer Center, Chiba, Japan.
11 Center for Preventive Medical Sciences, Chiba University, Chiba, Japan.
12 Laboratory for Structural Bioinformatics, RIKEN Center for Biosystems Dynamics Research, Kanagawa, Japan.
13 St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA.
14 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Necker Hospital for Sick Children, Paris, France.
15 University of Paris, Paris, France.
16 Howard Hughes Medical Institute, New York, NY, USA.
17 Department of Applied Genomics, Kazusa DNA Research Institute, Chiba, Japan.
18 Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. [email protected].
19 Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. [email protected].
# Contributed equally.

PMID: 34155405 DOI: 10.1038/s41590-021-00951-z

Abstract

In the present study, we report a human-inherited, impaired, adaptive immunity disorder, which predominantly manifested as a B cell differentiation defect, caused by a heterozygous IKZF3 missense variant, resulting in a glycine-to-arginine replacement within the DNA-binding domain of the encoded AIOLOS protein. Using mice that bear the corresponding variant and recapitulate the B and T cell phenotypes, we show that the mutant AIOLOS homodimers and AIOLOS-IKAROS heterodimers did not bind the canonical AIOLOS-IKAROS DNA sequence. In addition, homodimers and heterodimers containing one mutant AIOLOS bound to genomic regions lacking both canonical motifs. However, the removal of the dimerization capacity from mutant AIOLOS restored B cell development. Hence, the adaptive immunity defect is caused by the AIOLOS variant hijacking IKAROS function. Heterodimeric interference is a new mechanism of autosomal dominance that causes inborn errors of immunity by impairing protein function via the mutation of its heterodimeric partner.

Name
Email *

	Sorry, but the email address you supplied was invalid.