Datensatz

Zusammenfassung

The rare chromosome 2p16.1-p15 deletion syndrome (MIM 612513) is characterized by intellectual disability, dysmorphic features and microcephaly. A high proportion of affected individuals have autism, behavioral problems and language deficits. Skeletal and organ abnormalities have also been reported. Comparison of the chromosomal regions deleted in different cases suggests that haploinsufficiency of the zinc finger transcription factor BCL11A (MIM 606557) may underlie the neurological features of the syndrome. Although the role of BCL11A in brain development is poorly understood, the gene is expressed in the developing cortex, hippocampus, basal ganglia and cerebellum, and has recently been reported to play a role in the specification of subcortical projection neurons by repressing expression of TBR1 (MIM 604616), a gene recurrently mutated in cases of autism. In addition to its function in the brain, BCL11A has a key role in mediating the switch from the fetal to the adult form of hemoglobin, and persistence of fetal hemoglobin has been reported in several patients with BCL11A deletions. The first disorder-associated missense variants in BCL11A have recently been identified in three unrelated infants with developmental delay. The variants in these patients cluster within the N-terminal portion of the protein, and lie outside the zinc finger DNA-binding domains, in a region of unknown function. We therefore sought to characterize the effects of these variants on protein function in order to confirm their etiological role in disorder in these three patients, and to illuminate the molecular mechanism of disorder. We found that all three variants disrupt the localization of BCL11A within the nucleus and abolish protein dimerization and transcriptional regulatory activity. Our results therefore strongly support a causal role for BCL11A variants in the developmental delay in these patients, and add to the growing evidence that BCL11A is a recurrently mutated gene in neurodevelopmental disorder. Furthermore the characterization of these variants reveals a key role for the N-terminal region of BCL11A in mediating protein dimerization and regulation of transcription.