Congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1.

Master regulators, such as the hematopoietic transcription factor (TF) GATA1, play an essential role in orchestrating lineage commitment and differentiation. However, the precise mechanisms by which such TFs regulate transcription through interactions with specific cis-regulatory elements remain incompletely understood. Here, we describe a form of congenital hemolytic anemia caused by missense mutations in an intrinsically disordered region of GATA1, with a poorly understood role in transcriptional regulation. Through integrative functional approaches, we demonstrate that these mutations perturb GATA1 transcriptional activity by partially impairing nuclear localization and selectively altering precise chromatin occupancy by GATA1. These alterations in chromatin occupancy and concordant chromatin accessibility changes alter faithful gene expression, with failure to both effectively silence and activate select genes necessary for effective terminal red cell production. We demonstrate how disease-causing mutations can reveal regulatory mechanisms that enable the faithful genomic targeting of master TFs during cellular differentiation.

Pitfalls in diagnosing psychogenic nonepileptic seizures in a sexually abused child.

A six-year-old girl living in a residential care facility because of previous sexual abuse at home showed intractable seizures with epileptic discharges on interictal EEG. The features of the attacks were sudden impaired consciousness, only in daytime while eating, studying, and walking, with no motor acts and continuing for several minutes to one hour. She could not recall the attacks, and anticonvulsants showed no effects. She gradually became irritated and antisocial, exhibiting impulsive and hyperactive behavior. Interictal EEG repeatedly showed diffuse irregular spikes and wave complexes. The attacks continued sporadically for more than two years and ceased after disclosure of repeated sexual abuse by a boy at the residential care facility. In this case, delayed diagnosis of psychogenic nonepileptic seizures was associated with diagnostic difficulty of dissociative symptoms in a child, the presence of epileptiform EEG in an abused child, and undetected sexual abuse in a residential care facility, the potential for which pediatric neurologists should be aware. These pitfalls are discussed in the context of previous related literature.