Towards a new genetic player in the pathophysiology of Rett Syndrome

Rett Syndrome (RTT) is a severe neurodevelopmental disorder mainly prevalent in females who start exhibiting symptoms around 6 to 18 months. These include arrest of neurological development and loss of early acquired developmental skills. The majority of RTT cases arise from sporadic mutations within the gene coding for the methyl-CpG binding protein 2 (MeCP2). The latter is particularly abundant in neurons where it affects neuronal maturation and functioning. While several genes have been linked with RTTlike phenotypes over the years, Mecp2 remains the key player of the disorder. Previous efforts in the laboratory showed that the gene encoding for Hippocalcin-like 4 (HPCAL4) is consistently downregulated in the brain of RTT mice lacking Mecp2 and in primary neuronal cultures depicting the disorder. The protein is a member of the visinin-like proteins (VSNLs), a family of neuronal Ca2+ sensor proteins involved in Ca2+ dependant signalling cascades such as release of neurotransmitters. While other members of this protein family have been more studied and linked to some neurological disorders, the proper function of Hpcal4 beyond its involvement in calcium signalling isn’t well documented yet. Therefore, we aim to characterize this gene and potentially identify it as a new therapeutic target for RTT. By assessing protein expression, we found that it is regionally modulated alongside brain development and is reduced in the RTT mouse brain and in RTT neurons. We determined that the protein is enriched in the presynaptic compartment. We have identified several interactor proteins that have distinct functions related to neurotransmission. These findings, in addition to future work focused on investigating the phenotypical outcomes of Hpcal4 downregulation in neurons, will collectively elucidate its endogenous role and provide insights that will determine its potential association with RTT.