The first identified member of this constantly growing family is the UBE3A gene encoding the E6-AP HECT-type E3 ubiquitin ligase and whose loss-of-function has been shown to cause Angelman syndrome more than twenty years ago (Kishino et al., 1997; Matsuura et al., 1997; Sutcliffe et al., 1997). Here, UBE3A is linked to Angelman syndrome.