Identification of novel BCL11A variants in patients with epileptic encephalopathy: Expanding the phenotypic spectrum

Abstract

BCL11A encodes a zinc finger protein that is highly expressed in hematopoietic tissues and the brain, and that is known to function as a transcriptional repressor of fetal hemoglobin (HbF). Recently, de novo variants in BCL11A have been reported in individuals with intellectual disability syndrome without epilepsy. In this study, we performed whole-exome sequencing of 302 patients with epileptic encephalopathies (EEs), and identified 2 novel BCL11A variants, c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr). Both the patients shared major physical features characteristic of BCL11A-related intellectual disability syndrome, suggesting that characteristic physical features and the persistence of HbF should lead clinicians to suspect EEs caused by BCL11A pathogenic variants. Patient 1, with a frameshift variant, presented with Lennox-Gastaut syndrome, which expands the phenotypic spectrum of BCL11A haploinsufficiency. Patient 2, with a p.Lys784Thr variant, presented with West syndrome followed by drug-resistant focal seizures and more severe developmental disability. These 2 newly described patients contribute to delineating the associated, yet uncertain phenotypic characteristics of BCL11A disease-causing variants.

Long noncoding RNA CDKN2B‐AS1 interacts with transcription factor BCL11A to regulate progression of cerebral infarction through mediating MAP4K1 transcription

“…The findings of the current study confirmed that CDKN2B-AS1 could bind to and regulate the expression of a transcription factor BCL11A, which then can associate with the MAP4K1 promoter so as to inhibit the expression of MAP4K1. BCL11A, encoding an acetylene (Cys2-His2) zinc finger transcription factor, is widely expressed in hematopoietic cells as well as brain and recently emerged as a protein correlated with hematopoietic malignancies (41). BCL11A is up-regulated in several B-cell lymphomas resulting from chromosomal translocations (42).…”

“…MAP4K1, also considered to be a hematopoietic progenitor kinase 1 (43), has been demonstrated to participate in hematopoietic cell proliferation and apoptosis (18). Yoshida et al verified the vital roles of MAP4K4 and some lncRNAs in regulating embryo implantation (41). Strikingly, inflammation was reported to be one of the physiopathology processes to evaluate the pathogenesis of cerebral infarction (44).…”

“…Strikingly, inflammation was reported to be one of the physiopathology processes to evaluate the pathogenesis of cerebral infarction (44). TGF-b and IL-10 are both known to be immunosuppressive cytokines (41). Cruz et al (45) have indicated the involvement of IL-4 and TGF-b in neurogenesis.…”

Bcl11 Transcription Factors Regulate Cortical Development and Function

“…Recent reports examining patients carrying heterozygous Bcl11 mutations not only revealed severe defects of the immune system but also neurodevelopmental disorders including intellectual disabilities (Dias et al, 2016;Punwani et al, 2016;Lessel et al, 2018;Soblet et al, 2018;Yoshida et al, 2018;Peron et al, 2019). In the case of Bcl11a the mutations analyzed so far reside at the amino terminal end most likely preventing protein-protein interactions, e.g., homodimerization for nuclear localization and complex building of factors required for DNA binding, leading to impaired transcriptional regulation (Dias et al, 2016).…”

Recent progress in understanding and manipulating haemoglobin switching for the haemoglobinopathies

“…Since its discovery through human genetics, BCL11A, a zinc finger protein expressed in numerous tissues, has been validated as a repressor of HbF expression by knockdown and knockout in primary human erythroblasts, erythroid cell lines and mouse knockout models (Sankaran et al , , ; Bauer & Orkin, ; Canver et al , ). Naturally occurring rare variants, which were discovered in individuals with an autism‐like neurological syndrome (see below), have shown that haploinsufficiency of BCL11A results in derepression to about 15% HbF on average, a level similar to that of HPFH syndromes that protect against co‐inherited β‐haemoglobinopathies (Basak et al , ; Funnell et al , ; Dias et al , ; Yoshida et al , ).…”