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DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders.
Am. J. Hum. Genet. 112, 394-413 (2025)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Bcl11b ; C2h2-type Zinc Finger Protein ; Genotype-phenotype Correlation ; Recognition Code ; Type 2 Innate Lymphoid Cells
Language
english
Publication Year
2025
HGF-reported in Year
2025
ISSN (print) / ISBN
0002-9297
e-ISSN
1537-6605
Quellenangaben
Volume: 112,
Issue: 2,
Pages: 394-413
Publisher
Elsevier
Publishing Place
New York, NY
Reviewing status
Peer reviewed
Institute(s)
Institute of Neurogenomics (ING)
POF-Topic(s)
30205 - Bioengineering and Digital Health
Research field(s)
Genetics and Epidemiology
PSP Element(s)
G-503200-001
Scopus ID
85216622452
PubMed ID
39798569
Erfassungsdatum
2025-03-20