Involvement of ADGRV1 Gene in Familial Forms of Genetic Generalized Epilepsy

Abstract

Background: Genetic generalized epilepsies (GGE) including childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and GGE with tonic–clonic seizures alone (GGE-TCS), are common types of epilepsy mostly determined by a polygenic mode of inheritance. Recent studies showed that susceptibility genes for GGE are numerous, and their variants rare, challenging their identification. In this study, we aimed to assess GGE genetic etiology in a Sudanese population.Methods: We performed whole-exome sequencing (WES) on DNA of 40 patients from 20 Sudanese families with GGE searching for candidate susceptibility variants, which were prioritized by CADD software and functional features of the corresponding gene. We assessed their segregation in 138 individuals and performed genotype–phenotype correlations.Results: In a family including three sibs with GGE-TCS, we identified a rare missense variant in ADGRV1 encoding an adhesion G protein-coupled receptor V1, which was already involved in the autosomal recessive Usher type C syndrome. In addition, five other ADGRV1 rare missense variants were identified in four additional families and absent from 119 Sudanese controls. In one of these families, an ADGRV1 variant was found at a homozygous state, in a female more severely affected than her heterozygous brother, suggesting a gene dosage effect. In the five families, GGE phenotype was statistically associated with ADGRV1 variants (0R = 0.9 103).Conclusion: This study highly supports, for the first time, the involvement of ADGRV1 missense variants in familial GGE and that ADGRV1 is a susceptibility gene for CAE/JAE and GGE-TCS phenotypes.

Monitoring paxillin in astrocytes reveals the significance of the adhesion G protein coupled receptor VLGR1/ADGRV1 for focal adhesion assembly

“…In addition, it has been found that different mutations in mouse models for Vlgr1/Adgrv1 are associated with audiogenic epilepsy 3 . However, over the last years, there is also growing evidence that mutations in VLGR1/ADGRV1 also can cause different forms of epilepsy in humans 10,11 . Concrete knowledge of VLGR1's molecular function and signalling is necessary for gaining insights into the pathomechanisms and the elucidation of potential targets for therapies of diseases related to VLGR1.…”

The adhesion G-protein coupled receptor VLGR1/ADGRV1 controls autophagy

“…Besides USH2C, defects, namely haploinsufficiency of VLGR1/ADGRV1 can also lead to the development of epilepsy in humans 9,56 and audiogenic epilepsy in mice 2 . There is increasing evidence that alterations in autophagy are present in epileptogenesis, leading to imbalanced excitatory-inhibitory neurotransmission and epilepsy-induced neuronal damage 57,58 .…”

“…Mutations in the VLGR1/ADGRV1 gene cause Usher syndrome type 2C (USH2C) which is characterized by congenital sensorineural hearing loss and retinitis pigmentosa (RP) 7 . Additionally, mutations, even haploinsufficiency of VLGR1/ADGRV1 have been associated with different forms of epilepsy in humans and audiogenic seizures in mice (Dahawi et al 2021;Myers et al 2018; Zhou et al 2022). Almost nothing is known to date about the pathomechanisms underlying epileptogenesis that lead to the imbalance between excitatory and inhibitory neurotransmission described in epilepsy patients.…”

The adhesion GPCR VLGR1/ADGRV1 regulates focal adhesion turnover by controlling their assembly

“…In addition, it has been found that different mutations in mouse models for Vlgr1/Adgrv1 are associated with audiogenic epilepsy 9 . However, over the last years there is also growing evidence that mutations in VLGR1/ADGRV1 also can cause different forms of epilepsy in humans 12,13 . Concrete knowledge on VLGR1´s molecular function and signaling is necessary for gaining insights into the pathomechanisms and the elucidation of potential targets for therapies of diseases related to VLGR1.…”