HIVEP2 disorder is transmitted in an autosomal dominant manner. The vast majority of pathogenic variants reported in association with HIVEP2 disorder have been nonsense or frameshift variants, though other variant types underlying the disorder can include missense or canonical splice site variants.
The suspected pathophysiological mechanism is loss-of-function resulting in haploinsufficiency of HIVEP2. HIVEP2 is a member of the ZAS family of proteins containing zinc-finger domains, a serine/threonine-rich sequence, and an acidic region. HIVEP2 is a transcriptional regulator, implicated in processes like cell growth and development. In the brain, HIVEP2 activates expression of SSTR-2 (somatostatin receptor 2), which is a G-protein-coupled receptor that links the activity of somatostatin to effects on central nervous system activities like neurotransmitter release. Furthermore, HIVEP2 downregulates transcription of both c-Myc (implicated in cell growth, differentiation, and apoptosis) and genes in the NF-κB pathway (implicated in synaptic activity, among other roles).
Animal models have suggested that HIVEP2 may play a role in hippocampal development. Mice lacking Hivep2 exhibit various behavioural and learning issues, such as anxiety, hyperactivity, and working memory deficits. In these mice, there is evidence of abnormal maturation and synaptic plasticity of hippocampal neurons.