RIT2: responsible and susceptible gene for neurological and psychiatric disorders

Abstract

RIT2 gene was recently introduced as a susceptibility gene in neurological disorders, a group of major problems in human society affecting millions of people worldwide. Several variants, including single nucleotide polymorphisms and CNVs, have been identified and studied in different populations. In this review, we have summarized the studies relevant to the RIT2 gene and its related disorders, including Parkinson's disease, schizophrenia, and autism. The protein product of RIT2 is a member of the Ras superfamily that plays important roles in many vital cellular functions, such as differentiation and survival. We have also investigated the protein network of the RIT2 protein and the diseases related to members of this network so as to obtain some clues for future studies by identifying the molecular pathophysiology of neurological disorders and revealing new possible disorders related to RIT2.

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

“…Rin is involved in calcium-mediated processes in cells and binds to calmodulin through a C-terminal binding motif, regulating the Rin-mediated pathway (Hoshino and Nakamura, 2002; Daneshmandpour et al, 2018). Rin has an important role in intracellular signaling and interacts with DAT (dopamine active transporter) in lipid raft microdomains (Navaroli et al, 2011).…”

“…Recent genome wide association study (GWAS) and meta-analysis results introduced Rit2 as a novel susceptibility locus, in association with decreased Rin expression in the substantia nigra pars compacta (SNc) of PD patients (Bossers et al, 2009; Latourelle et al, 2012; Pankratz et al, 2012). However, the results of RIT2 polymorphisms studies in different populations are controversial, which may be due to genetic context difference and environmental factors (Daneshmandpour et al, 2018). Therefore, further functional study, animal study and larger study with various population samples might give more detailed role of RIT2 in cells and groups in PD pathogenesis.…”

“…Selected members of Ras subfamily and their related possible interacting proteins are listed in the Table 2. Specifically for RIT2, evidence suggests that proteins interacting with RIT2 may cause or relate to similar clinical signs or diseases, which implied that RIT2 might be a potential candidate gene underlying several neurological diseases, such as PD, schizophrenia and autism (Daneshmandpour et al, 2018).…”

Conditional, inducible gene silencing in dopamine neurons reveals a sex-specific role for Rit2 GTPase in acute cocaine response and striatal function

“…The neuronal, Ras-like GTPase, Rit2 (aka: Rin, ras-like in neurons), is enriched in DANs [8] and is required for NGF-mediated MAP kinase activation in neuroendocrine cells [9,10]. Multiple genome-wide association studies (GWAS) identified Rit2 in several DA-related disorders, including PD [11], ASD [12], essential tremor, schizophrenia, and bipolar disorder [13][14][15]. We previously demonstrated that Rit2 binds directly to the presynaptic, cocaine-sensitive DAT, and that Rit2 activity is required for PKC-stimulated DAT endocytosis in cell lines [16].…”

Fine-grained deconvolution of cell-type effects from human bulk brain data using a large single-nucleus RNA sequencing based reference panel

“…Six of the ten genes were previously reported to be associated with a range of psychiatric and neurological disorders. In addition to NRG1 46,47 , this included ZNF804B 48 , CDH12 49 , CLSTN2 50,51 , RIT2 52 , and MCTP1 53 . This pattern is somewhat reminiscent of so-called Von Economo neurons (VENs) that are known to be altered in diseases such as Alzheimer, autism, and schizophrenia 54-56 .…”