The candidate mutations identified in this study implicate several candidate genes in autism that encode proteins involved in small GTPase mediated signal transduction, transcriptional regulation, and protein modification processes (Table 2). Among the mutations we identified is a homozygous c.144 C>T change that creates an R40C mutation in ubiquitin protein ligase E3B (UBE3B), a member of the E3 ubiquitin-conjugating enzyme family. UBE3B is highly expressed in the brain and may play a role in stress response [25]. The UBE3B R40C mutation identified in AU035204 is predicted to be damaging, was homozygous in both affected children (monozygotic twins), heterozygous in the parents and unaffected sibling (Figure S2), and was absent in the homozygous state in 1344 control chromosomes. UBE3B is highly conserved across species and belongs to the same family as UBE3A, the gene disrupted in Angelman syndrome, a neurodevelopmental disorder characterized by intellectual disability, movement or balance problems, abnormal behaviors, and speech and language impairment. Recent work has shown that experience-driven neuronal activity induces Ube3a transcription and that it regulates excitatory synapse development and function through targeting the key synaptic molecules Arc and Ephexin5 [26], [27].
