MDN1 variants cause susceptibility to epilepsy

Acta Epileptologica, Год журнала: 2025, Номер 7(1)

Опубликована: Март 3, 2025

Abstract Background The Midasin AAA (ATPase associated with various activities) ATPase 1 ( MDN1 ) gene, a member of the protein family, plays crucial role in ribosome maturation. is expressed human brain throughout life, especially during early development and adulthood. However, variants have not been previously reported patients epilepsy. This study aims to explore association between Methods Trios-based whole-exome sequencing was performed cohort epilepsy susceptibility from China Epilepsy Gene 1.0 Project. excess, damaging effects, molecular subregional implications variants, as well spatio-temporal expression , were analyzed validate gene-disease association. Results Compound heterozygous identified five unrelated febrile seizures or secondary Three presented seizures/epilepsy plus, while two developed damage (five seven years after). These either absent present at low frequencies control group, exhibited statistically significant higher case group compared controls. All missense predicted be by least one silico tool. In each pair compound allele located AAA2-AAA3 domains, other linker domain its vicinity. contrast, most asymptomatic outside suggesting implication variants. Conclusions potentially gene for

Язык: Английский

CSMD1 is a causative gene of developmental and epileptic encephalopathy and generalized epilepsies

Genes & Diseases, Год журнала: 2024, Номер 12(4), С. 101473 - 101473

Опубликована: Ноя. 29, 2024

Genetic factors are the major causes of epilepsies, such as developmental and epileptic encephalopathy (DEE) idiopathic generalized epilepsy (IGE). However, etiology most patients remains elusive. This study performed exon sequencing in a cohort 173 with IGE. Additional cases were recruited from matching platform China. The excess damaging effect variants, genotype-phenotype correlation, correlation between gene expression phenotype studied to validate gene-disease association. CSMD1 compound heterozygous variants identified four unrelated five DEE featured by seizures platform, including two de novo three variants. Two refractory antiseizure medications all on long-term therapy. presented significantly high case-cohort. Besides origination, had each paired located closer other than IGE or more significant alterations hydrophobicity. DEE-associated absent normal population lower minor allele frequency IGE-associated suggesting frequency-phenotype severity correlation. Gene analysis showed that was extensively expressed throughout brain, particularly cortex. temporal pattern correlated disease onset outcomes. suggests is associated novel causative epilepsies.

Язык: Английский

Analysis of 14q12 microdeletions reveals novel regulatory loci for the neurodevelopmental disorder-related gene,FOXG1

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Апрель 17, 2025

Abstract Structural variants (SVs) are genetic that can vary widely in size, but generally greater than 50bp. While there many different types of SVs, deletions perhaps the easiest to interpret given loss material. As such up 17% neurodevelopmental disorders (NDDs) be explained by SVs disrupt coding regions causing gene dosage defects. Conversely, contribution non-coding etiology NDDs is unknown., From a few NDDs, and other mendelian we know perturb cis -regulatory elements (CREs) downstream expression. In this study, identified multiple 14q12 region NDD-related FOXG1 individuals with epilepsy, microcephaly, intellectual disability (ID) and/or developmental delays. This encodes transcription factor essential for cerebral corticogenesis, haploinsufficiency associated epilepsy NDDs. To test whether alter expression, chose minimum overlapping these (MRO), modeled deletion HAP1s, haploid line expressing . Deletion MRO reduced mRNA protein levels, while altering FOXG1’s native genomic interactions. We at least two novel putative CREs propose coregulate Moreover, changes transcriptomic profiles seen overlap part loss, indicating converging molecular pathways haploinsufficiency. These findings expand scope complex regulatory mechanisms, more broadly, NDD susceptibility. A comprehensive understanding will enable identification potential targets gene-targeting therapies, including FOXG1-related

Язык: Английский