DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders
Creators: name: Lessel, Ivana
name: Baresic, Anja
name: Chinn, Ivan K.
name: May, Jonathan
name: Goenka, Anu
name: Chandler, Kate E.
name: Posey, Jennifer E.
name: Afenjar, Alexandra
name: Averdunk, Luisa
name: Bedeschi, Maria Francesca
name: Besnard, Thomas
name: Brager, Rae
name: Brick, Lauren
name: Brugger, Melanie
name: Brunet, Theresa
name: Byrne, Susan
name: Calle-Martín, Oscar de la
name: Capra, Valeria
name: Cardenas, Paul
name: Chappé, Céline
name: Chong, Hey J.
name: Cogne, Benjamin
name: Conboy, Erin
name: Cope, Heidi
name: Courtin, Thomas
name: Deb, Wallid
name: Dilena, Robertino
name: Dubourg, Christèle
name: Elgizouli, Magdeldin
name: Fernandes, Erica
name: Fitzgerald, Kristi K.
name: Gangi, Silvana
name: George-Abraham, Jaya K.
name: Gucsavas-Calikoglu, Muge
name: Haack, Tobias B.
name: Hadonou, Medard
name: Hanker, Britta
name: Hüning, Irina
name: Iascone, Maria
name: Isidor, Bertrand
name: Järvelä, Irma
name: Jin, Jay J.
name: Jorge, Alexander A.L.
name: Josifova, Dragana
name: Kalinauskiene, Ruta
name: Kamsteeg, Erik-Jan
name: Keren, Boris
name: Kessler, Elena
name: Kölbel, Heike
name: Kozenko, Mariya
name: Kubisch, Christian
name: Kuechler, Alma
name: Leal, Suzanne M.
name: Leppälä, Juha
name: Luu, Sharon M.
name: Lyon, Gholson J.
name: Madan-Khetarpal, Suneeta
name: Mancardi, Margherita
name: Marchi, Elaine
name: Mehta, Lakshmi
name: Menendez, Beatriz
name: Morel, Chantal F.
name: Harasink, Sue Moyer
name: Nevay, Dayna-Lynn
name: Nigro, Vincenzo
name: Odent, Sylvie
name: Oegema, Renske
name: Pappas, John
name: Pastore, Matthew T.
name: Perilla-Young, Yezmin
name: Platzer, Konrad
name: Powell-Hamilton, Nina
name: Rabin, Rachel
name: Rekab, Aisha
name: Rezende, Raissa C.
name: Robert, Leema
name: Romano, Ferruccio
name: Scala, Marcello
name: Poths, Karin
name: Schrauwen, Isabelle
name: Sebastian, Jessica
name: Short, John
name: Sidlow, Richard
name: Sullivan, Jennifer
name: Szakszon, Katalin
name: Tan, Queenie K.G.
name: Wagner, Matias
name: Wieczorek, Dagmar
name: Yuan, Bo
name: Maeding, Nicole
name: Strunk, Dirk
name: Begtrup, Amber
name: Banka, Siddharth
name: Lupski, James R.
name: Tolosa, Eva
name: Lessel, Davor
Publisher: name: Universität Regensburg
Year: 2025
Subjects: subject: BCL11B; C2H2-type zinc finger protein; recognition code; genotype-phenotype correlation; type 2 innate lymphoid cells
subject: 610 Medizin

description: 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 zinc-binding 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 α helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, 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.