Lessel, Ivana and Baresic, Anja and Chinn, Ivan K. and May, Jonathan and Goenka, Anu and Chandler, Kate E. and Posey, Jennifer E. and Afenjar, Alexandra and Averdunk, Luisa and Bedeschi, Maria Francesca and Besnard, Thomas and Brager, Rae and Brick, Lauren and Brugger, Melanie and Brunet, Theresa and Byrne, Susan and de la Calle-Martin, Oscar and Capra, Valeria and Cardenas, Paul and Chappe, Celine and Chong, Hey J. and Cogne, Benjamin and Conboy, Erin and Cope, Heidi and Courtin, Thomas and Deb, Wallid and Dilena, Robertino and Dubourg, Christele and Elgizouli, Magdeldin and Fernandes, Erica and Fitzgerald, Kristi K. and Gangi, Silvana and George-Abraham, Jaya K. and Gucsavas-Calikoglu, Muge and Haack, Tobias B. and Hadonou, Medard and Hanker, Britta and Huning, Irina and Iascone, Maria and Isidor, Bertrand and Jarvela, Irma and Jin, Jay J. and Jorge, Alexander A. L. and Josifova, Dragana and Kalinauskiene, Ruta and Kamsteeg, Erik-Jan and Keren, Boris and Kessler, Elena and Koelbel, Heike and Kozenko, Mariya and Kubisch, Christian and Kuechler, Alma and Leal, Suzanne M. and Leppala, Juha and Luu, Sharon M. and Lyon, Gholson J. and Madan-Khetarpal, Suneeta and Mancardi, Margherita and Marchi, Elaine and Mehta, Lakshmi and Menendez, Beatriz and Morel, Chantal F. and Harasink, Sue Moyer and Nevay, Dayna-Lynn and Nigro, Vincenzo and Odent, Sylvie and Oegema, Renske and Pappas, John and Pastore, Matthew T. and Perilla-Young, Yezmin and Platzer, Konrad and Powell-Hamilton, Nina and Rabin, Rachel and Rekab, Aisha and Rezende, Raissa C. and Robert, Leema and Romano, Ferruccio and Scala, Marcello and Poths, Karin and Schrauwen, Isabelle and Sebastian, Jessica and Short, John and Sidlow, Richard and Sullivan, Jennifer and Szakszon, Katalin and Tan, Queenie K. G. and Wagner, Matias and Wieczorek, Dagmar and Yuan, Bo and Maeding, Nicole and Strunk, Dirk and Begtrup, Amber and Banka, Siddharth and Lupski, James R. and Tolosa, Eva and Lessel, Davor (2025) DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders. AMERICAN JOURNAL OF HUMAN GENETICS, 112 (2). pp. 394-413. ISSN 0002-9297, 1537-6605
Full text not available from this repository. (Request a copy)Abstract
BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zincbinding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting a helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to lateonset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and ''specificity residues'' impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TRANSCRIPTION FACTOR BCL11B; DIFFERENTIATION; MUTATIONS; ARCHITECTURE; CHECKPOINT; CELLS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Mar 2026 08:21 |
| Last Modified: | 30 Mar 2026 08:21 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67933 |
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