Mutacja genu RLIM związana z epilepsją dziedziczoną z chromosomu X oraz zaburzeniami rozwojowymi - wpływ lokalizacji mutacji na nasilenie choroby
RLIM variant associated with X-linked epilepsy with neurodevelopmental disorders and the molecular sub-regional effects
W skrócie
Badacze znaleźli u czterech chłopców mutacje w genie RLIM powodujące epilepsję pojawiającą się między 13. a 36. miesiącem życia. Okazało się, że miejsce, gdzie znajduje się mutacja w genie, decyduje o nasileniu choroby - mutacje w pewnych obszarach genu powodują cięższe zaburzenia rozwojowe, a w innych łagodniejsze objawy z opóźnieniami w mowie i motoryce. Gen RLIM jest szczególnie aktywny w rozwijającym się mózgu i odpowiada za prawidłowy rozwój mózgu oraz kontrolę napadów padaczkowych.
Oryginalny abstract (angielski)
PURPOSE: RLIM encodes an E3 ubiquitin ligase associated with Tonne-Kalscheuer syndrome (TOKAS) with occasional seizures, but its roles in epilepsy are unelucidated. This study aimed to explore the association of RLIM with epilepsy. METHODS: Trio-based whole-exome sequencing was performed in patients with unknown causes. We systematically reviewed reported RLIM variants for genotype-phenotype correlations. Spatiotemporal expression profiles and protein-protein interaction network enrichment were investigated to explore the underlying mechanisms of phenotypic features. RESULTS: Four hemizygous RLIM missense variants were identified in four unrelated male patients, which are absent in gnomAD controls. All variants altered amino acid hydrophobicity/protein stability and localized to mutation-intolerant regions. All patients had early-onset epilepsy (13-36 months). Case 3 with a variant in the basic domain (BD) had developmental and epileptic encephalopathy, while other patients with variants in other regions presented milder epilepsy with motor/speech delay. Analysis of 13 additional variants indicated possible molecular subregional effects: BD/RING variants caused severe/fatal developmental disorders, while N-terminal variants had milder phenotypes. RLIM was highly expressed in the developing brain and showed high expression in neurons, suggesting its vital role in neurodevelopment. RLIM exhibited an increased expression after late childhood, indicating an increased functional dependence in the late stage, which is consistent with the phenotype of seizure relapse. Its protein-protein interaction(PPI) network contained 72 nodes, interacting with epilepsy/neurodevelopmental disorders (NDDs) causative genes. CONCLUSIONS: RLIM variants are associated with X-linked epilepsy with NDDs. Molecular subregional effects, genotype-phenotype association, and expression-phenotype correlations provide critical insights into the clinical diagnosis, management and mechanistic investigation of RLIM-related disorders.