Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies. Blood 2021 Jan 21;137(3):349-363
Date
08/28/2020Pubmed ID
32845957Pubmed Central ID
PMC7819759DOI
10.1182/blood.2020007292Scopus ID
2-s2.0-85098538966 (requires institutional sign-in at Scopus site) 35 CitationsAbstract
IKAROS is a transcription factor forming homo- and heterodimers and regulating lymphocyte development and function. Germline mutations affecting the IKAROS N-terminal DNA binding domain, acting in a haploinsufficient or dominant-negative manner, cause immunodeficiency. Herein, we describe 4 germline heterozygous IKAROS variants affecting its C-terminal dimerization domain, via haploinsufficiency, in 4 unrelated families. Index patients presented with hematologic disease consisting of cytopenias (thrombocytopenia, anemia, neutropenia)/Evans syndrome and malignancies (T-cell acute lymphoblastic leukemia, Burkitt lymphoma). These dimerization defective mutants disrupt homo- and heterodimerization in a complete or partial manner, but they do not affect the wild-type allele function. Moreover, they alter key mechanisms of IKAROS gene regulation, including sumoylation, protein stability, and the recruitment of the nucleosome remodeling and deacetylase complex; none affected in N-terminal DNA binding defects. These C-terminal dimerization mutations are largely associated with hematologic disorders, display dimerization haploinsufficiency and incomplete clinical penetrance, and differ from previously reported allelic variants in their mechanism of action. Dimerization mutants contribute to the growing spectrum of IKAROS-associated diseases displaying a genotype-phenotype correlation.
Author List
Kuehn HS, Niemela JE, Stoddard J, Mannurita SC, Shahin T, Goel S, Hintermeyer M, Heredia RJ, Garofalo M, Lucas L, Singh S, Tondo A, Jacobs Z, Gahl WA, Latour S, Verbsky J, Routes J, Cunningham-Rundles C, Boztug K, Gambineri E, Fleisher TA, Chandrakasan S, Rosenzweig SDAuthor
James Verbsky MD, PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Aged
Amino Acid Sequence
Base Sequence
Centromere
Chromosome Segregation
DNA
Female
Gene Expression Regulation
Germ Cells
Haploinsufficiency
Hematologic Neoplasms
Heterochromatin
Histone Deacetylase 1
Humans
Ikaros Transcription Factor
Male
Middle Aged
Mutant Proteins
Mutation
Pedigree
Protein Binding
Protein Multimerization
Protein Processing, Post-Translational
RNA, Messenger
Sumoylation
Transcription, Genetic
