TY - JOUR
T1 - DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders
AU - Undiagnosed Diseases Network
AU - Lessel, Ivana
AU - Baresic, Anja
AU - Chinn, Ivan K
AU - May, Jonathan
AU - Goenka, Anu
AU - Chandler, Kate E
AU - Posey, Jennifer E
AU - Afenjar, Alexandra
AU - Averdunk, Luisa
AU - Bedeschi, Maria Francesca
AU - Besnard, Thomas
AU - Brager, Rae
AU - Brick, Lauren
AU - Brugger, Melanie
AU - Brunet, Theresa
AU - Byrne, Susan
AU - Calle-Martín, Oscar de la
AU - Capra, Valeria
AU - Cardenas, Paul
AU - Chappé, Céline
AU - Chong, Hey J
AU - Cogne, Benjamin
AU - Conboy, Erin
AU - Cope, Heidi
AU - Courtin, Thomas
AU - Deb, Wallid
AU - Dilena, Robertino
AU - Dubourg, Christèle
AU - Elgizouli, Magdeldin
AU - Fernandes, Erica
AU - Fitzgerald, Kristi K
AU - Gangi, Silvana
AU - George-Abraham, Jaya K
AU - Gucsavas-Calikoglu, Muge
AU - Haack, Tobias B
AU - Hadonou, Medard
AU - Hanker, Britta
AU - Hüning, Irina
AU - Iascone, Maria
AU - Isidor, Bertrand
AU - Järvelä, Irma
AU - Jin, Jay J
AU - Jorge, Alexander A L
AU - Josifova, Dragana
AU - Kalinauskiene, Ruta
AU - Kamsteeg, Erik-Jan
AU - Keren, Boris
AU - Kessler, Elena
AU - Kölbel, Heike
AU - Banka, Siddharth
N1 - Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2025/1/3
Y1 - 2025/1/3
N2 - 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.
AB - 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.
U2 - 10.1016/j.ajhg.2024.12.012
DO - 10.1016/j.ajhg.2024.12.012
M3 - Article
C2 - 39798569
SN - 0002-9297
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
ER -