ABSTRACT
Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.
Subject(s)
Carrier Proteins/genetics , Haploinsufficiency/genetics , Intellectual Disability/genetics , Neurodevelopmental Disorders/genetics , Nuclear Proteins/genetics , Transcription Factors/genetics , Transcription, Genetic , Animals , Carrier Proteins/chemistry , Carrier Proteins/metabolism , Cerebral Cortex/metabolism , Chromatin Assembly and Disassembly/genetics , Codon, Nonsense/genetics , Cognition Disorders/genetics , Frameshift Mutation/genetics , Hippocampus/metabolism , Humans , Intellectual Disability/pathology , Intellectual Disability/psychology , Male , Mice , Microcephaly/genetics , Mutation, Missense/genetics , Neurodevelopmental Disorders/pathology , Neurodevelopmental Disorders/physiopathology , Nuclear Proteins/chemistry , Nuclear Proteins/metabolism , Phenotype , Repressor Proteins , Social Behavior , Syndrome , Transcription Factors/chemistry , Transcription Factors/metabolism , TranscriptomeABSTRACT
Inflammation is an important contributor to pediatric and adult neurodegeneration. Understanding the genetic determinants of neuroinflammation provides valuable insight into disease mechanism. We characterize a disorder of recurrent immune-mediated neurodegeneration. We report two sisters who presented with neurodegeneration triggered by infections. The proband, a previously healthy girl, presented at 22.5 months with ataxia and dysarthria following mild gastroenteritis. MRI at onset showed a symmetric signal abnormality of the cerebellar and peritrigonal white matter. Following a progressive course of partial remissions and relapses, she died at 5 years of age. Her older sister had a similar course following varicella infection, she died within 13 months. Both sisters had unremarkable routine laboratory testing, with exception of a transient mild cytopenia in the proband 19 months after presentation. Exome sequencing identified a biallelic perforin1 mutation (PRF1; p.R225W) previously associated with familial hemophagocytic lymphohistiocytosis (FHL). In contrast to FHL, these girls did not have hematopathology or cytokine overproduction. However, 3 years after disease onset, the proband had markedly deficient interleukin-1 beta (IL-1ß) production. These observations extend the spectrum of disease associated with perforin mutations to immune-mediated neurodegeneration triggered by infection and possibly due to primary immunodeficiency.
