Induced pluripotent stem cells for modeling Angelman syndrome

Angelman syndrome (AS) is an incurable neurodevelopmental disease characterized by serious developmental delay, impaired speech, motor incoordination, and frequent atypical episodes of smiling and laughter. This disease is caused by loss of function of the maternally inherited UBE3A allele. This gene is submitted to imprinting regulation, being exclusively expressed from the maternal allele in mature neurons. Paternal UBE3A silencing involves the SNHG14 antisense noncoding RNA that is expressed exclusively from the paternal allele in neurons. UBE3A encodes for an E3 ubiquitin ligase involved in targeting specific proteins to proteasomal degradation being also potentially implicated in other molecular pathways. Most of our current understanding of the pathophysiology of AS has been gathered from seminal studies using maternal UBE3A null mouse models. However, several hurdles subsist to the direct translation of mouse studies to human patients, urging for the need of humanized models for this disease. The advent of induced pluripotent stem cells (iPSCs) and the continuing improvement of protocols for neuronal differentiation, including three-dimensional brain-in-a-dish models, created an alternative system to study molecular and cellular mechanisms underlying the pathology of neurodevelopmental diseases such as AS. Here, we document the available iPSC lines derived from AS patients that cover all the (epi) genetic causes of the disease and sum up the new knowledge brought by their study so far. Although still in its infancy, we believe iPSC technology will prove to be an important model system not only to understand the pathophysiological mechanisms underlying this disease but also as a valuable platform for drug screening/development in the context of AS therapy.