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

description: <p>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 &alpha; 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.</p>