EFHC1, Implicated in Juvenile Myoclonic Epilepsy, Functions at the Cilium and Synapse to Modulate Dopamine Signaling

Neurons throughout the mammalian brain possess non-motile cilia, organelles with varied functions in sensory physiology and cellular signaling. Yet, the roles of cilia in these neurons are poorly understood. To shed light into their functions, we studied EFHC1, an evolutionarily conserved protein required for motile cilia function and linked to a common form of inherited epilepsy in humans, juvenile myoclonic epilepsy (JME). We demonstrate that C. elegans EFHC-1 functions within specialized non-motile mechanosensory cilia, where it regulates neuronal activation and dopamine signaling. EFHC-1 also localizes at the synapse, where it further modulates dopamine signaling in cooperation with the orthologue of an R-type voltage-gated calcium channel. Our findings unveil a previously undescribed dual-regulation of neuronal excitability at sites of neuronal sensory input (cilium) and neuronal output (synapse). Such a distributed regulatory mechanism may be essential for establishing neuronal activation thresholds under physiological conditions, and when impaired, may represent a novel pathomechanism for epilepsy

Novel variant in glycophorin c gene protects against ribavirin-induced anemia during chronic hepatitis C treatment

Background: The current use of ribavirin in difficult-to-cure chronic hepatitis C patients (HCV) and patients with severe respiratory infections is constrained by the issue of ribavirin-induced hemolytic anemia that affects 30% of treated patients, requiring dosage modification or discontinuation. Though some genetic variants have been identified predicting this adverse effect, known clinical and genetic factors do not entirely explain the risk of ribavirin-induced anemia. Methods: We assessed the associations of previously identified variants in inosine triphosphatase (ITPA), solute carrier 28A2 (SLC28A2) and vitamin D receptor (VDR) genes with ribavirin-induced anemia defined as hemoglobin decline of ≥30 g/L on treatment, followed by a staged discovery (n = 114), replication (n = 74), and combined (n = 188) genome-wide association study to uncover potential new predictive variants. Results: We identified a novel association in the gene coding glycophorin C (rs6741425; OR:0.12, 95%CI:0.04–0.34, P = 2.94 × 10-6) that predicts protection against ribavirin-induced anemia. We also replicated the associations of ITPA and VDR genetic variants with the development of ribavirin-induced anemia (rs1127354; OR:0.13, 95%CI:0.04–0.41, P = 8.66 ×10-5; and rs1544410; OR:1.65, 95%CI:1.01–2.70, P = 0.0437). Conclusions: GYPC variation affecting erythrocyte membrane strength is important in predicting risk for developing ribavirin-induced anemia. ITPA and VDR genetic variants are also important predictors of this adverse reaction

Role of Cisplatin Dose Intensity and <i>TPMT </i>Variation in the Development of Hearing Loss in Children

Background:Cisplatin, widely used in the treatment of solid tumors, causes permanent hearing loss in more than 60% of treated children. Previous studies have implicated several clinical factors in the development of ototoxicity, including cumulative cisplatin dose. However, the role of cisplatin dose intensity in the development of hearing loss in children remains unclear. Pharmacogenetic studies have also identified genetic variants in TPMT that increase the risk of cisplatin-induced hearing loss. This study aims to determine whether cisplatin dose intensity contributes to the risk of hearing loss in children and whether genetic variations in TPMT further modifies the risk of cisplatin-induced hearing loss.Methods:The authors genotyped 371 cisplatin-treated children for the presence of any 3 TPMT-risk variants. Patients were categorized into high-, moderate-, and low-intensity cisplatin dosing groups according to the cisplatin dose administered per unit time. Kaplan-Meier curves were plotted to compare the cumulative incidence of hearing loss between the genotype and dose intensity groups.Results:Patients receiving cisplatin at high dose intensity experienced significantly higher incidences of ototoxicity than those receiving cisplatin at low dose intensity (P = 9 × 10-7). Further stratification by TPMT genotype revealed that carriers of ≥1 TPMT variants receiving high-intensity cisplatin developed ototoxicity sooner and more often than their wild-type counterparts (93.8% vs. 56.6% at 12 months; P = 5 × 10-5) and noncarriers receiving low-intensity cisplatin (21.2% at 12 months).Conclusions:Cisplatin dose intensity is strongly associated with ototoxicity development in children, and this risk is further increased by the presence of TPMT-risk alleles.</p

Role of Cisplatin Dose Intensity and TPMT Variation in the Development of Hearing Loss in Children

Background:Cisplatin, widely used in the treatment of solid tumors, causes permanent hearing loss in more than 60% of treated children. Previous studies have implicated several clinical factors in the development of ototoxicity, including cumulative cisplatin dose. However, the role of cisplatin dose intensity in the development of hearing loss in children remains unclear. Pharmacogenetic studies have also identified genetic variants in TPMT that increase the risk of cisplatin-induced hearing loss. This study aims to determine whether cisplatin dose intensity contributes to the risk of hearing loss in children and whether genetic variations in TPMT further modifies the risk of cisplatin-induced hearing loss.Methods:The authors genotyped 371 cisplatin-treated children for the presence of any 3 TPMT-risk variants. Patients were categorized into high-, moderate-, and low-intensity cisplatin dosing groups according to the cisplatin dose administered per unit time. Kaplan-Meier curves were plotted to compare the cumulative incidence of hearing loss between the genotype and dose intensity groups.Results:Patients receiving cisplatin at high dose intensity experienced significantly higher incidences of ototoxicity than those receiving cisplatin at low dose intensity (P = 9 × 10-7). Further stratification by TPMT genotype revealed that carriers of ≥1 TPMT variants receiving high-intensity cisplatin developed ototoxicity sooner and more often than their wild-type counterparts (93.8% vs. 56.6% at 12 months; P = 5 × 10-5) and noncarriers receiving low-intensity cisplatin (21.2% at 12 months).Conclusions:Cisplatin dose intensity is strongly associated with ototoxicity development in children, and this risk is further increased by the presence of TPMT-risk alleles

Data from: EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling

Neurons throughout the mammalian brain possess non-motile cilia, organelles with varied functions in sensory physiology and cellular signaling, yet their roles in these neurons are poorly understood. To shed light into their functions, we studied EFHC1, an evolutionarily conserved protein required for motile cilia function and linked to a common form of inherited epilepsy in humans, juvenile myoclonic epilepsy (JME). We demonstrate that C. elegans EFHC1 functions within specialized non-motile mechanosensory cilia, where it regulates neuronal activation and dopamine signaling. EFHC1 also localizes at the synapse, where it further modulates dopamine signaling in cooperation with the orthologue of an R-type voltage-gated calcium channel. Our findings unveil a previously undescribed dual-regulation of neuronal excitability at sites of neuronal sensory input (cilium) and neuronal output (synapse). Such a distributed regulatory mechanism may be essential for establishing neuronal activation thresholds under physiological conditions, and when impaired, may represent a novel pathomechanism for epilepsy

PACRG, a protein linked to ciliary motility, mediates cellular signaling

Cilia are microtubule-based organelles that project from nearly all mammalian cell types. Motile cilia generate fluid flow, whereas nonmotile (primary) cilia are required for sensory physiology and modulate various signal transduction pathways. Here we investigate the nonmotile ciliary signaling roles of parkin coregulated gene (PACRG), a protein linked to ciliary motility. PACRG is associated with the protofilament ribbon, a structure believed to dictate the regular arrangement of motility-associated ciliary components. Roles for protofilament ribbon-associated proteins in nonmotile cilia and cellular signaling have not been investigated. We show that PACRG localizes to a small subset of nonmotile cilia in Caenorhabditis elegans, suggesting an evolutionary adaptation for mediating specific sensory/signaling functions. We find that it influences a learning behavior known as gustatory plasticity, in which it is functionally coupled to heterotrimeric G-protein signaling. We also demonstrate that PACRG promotes longevity in C. Elegans by actiong upstream of the lifespan-promoting FOXO transcription factor DAF-16 and likely upstream of insulin/IGF signaling. Our findings establish previously unrecognized sensory/signaling functions for PACRG and point to a role for this protein in promoting longevity. Furthermore, our work suggests additional ciliary motility-signaling connections, since EFHC1 (EF-hand containing 1), a potential PACRG interaction partner similarly associated with the protofilament ribbon and ciliary motility, also positively regulates lifespan

Evaluating gene-disease relationships in motile ciliopathies: an international ClinGen and BEAT-PCD ERS CRC collaboration.

International audienceGenetic diagnosis of motile ciliopathies is conducted by healthcare, commercial and private laboratories. 88 genes have been implicated in motile ciliopathies (PCD, male infertility and associated disorders). Gene-disease relationships are uncertain where evidence is limited, risking inaccurate reporting and diagnosis. The ClinGen Motile Ciliopathy Gene Curation Expert Panel (GCEP) was set up collaboratively with BEAT-PCD ERS CRC in 2021. The GCEP comprises geneticists, pulmonologists and biocurators (Canada, France, Germany, Norway, Poland, Spain, Tunisia, UK, USA) tasked with classifying clinical validity of gene-disease relationships in motile ciliopathies to aid interpretation of genetic results. As an early step, the GCEP drew up guidelines to capturethe critical details of motile ciliopathy cases and to score genetic and experimental evidence conservatively and consistently. The GCEP meets monthly and so far has curated 33 gene-disease relationships (https://clinicalgenome.org/affiliation/40102/). 22 curations have reached a definitive classification as the role of the gene in disease has been repeatedly demonstrated and upheld over time, 4 were disputed.Classification PCD Infertility PCD InfertilityDefinitive CCDC39 CCDC40 CCDC103 CCNO CFAP43 DNAH1 DNAH17 CFAP300 DNAAF3 DNAH11 DNAH5 DNAI1 DNAI2 HYDIN MCIDAS ODAD1 ODAD2 ODAD4 RSPH1 RSPH4A SPAG1 ZMYND10Strong FOXJ1 DNAH8Limited CFAP57 DNAH1 DNAL1 GAS2L2 CFAP47These efforts provide a basis for future classifications of gene-disease relationships. The goal of the GCEP is to leverage emerging research to enhance the reliability of genetic testing for improved clinical detection and diagnosis of motile ciliopathies

CYP2D6 as a treatment decision aid for ER-positive non-metastatic breast cancer patients: a systematic review with accompanying clinical practice guidelines

10.1007/s10549-018-5027-0BREAST CANCER RESEARCH AND TREATMENT1733521-53