A de novo pathogenic variant in MICAL-1 causes epilepsy with auditory features.
MICAL‐1 oxidoreductase activity
epilepsy with auditory features (EAF)
genetics
novel pathogenic variant
sporadic patient
Journal
Epilepsia open
ISSN: 2470-9239
Titre abrégé: Epilepsia Open
Pays: United States
ID NLM: 101692036
Informations de publication
Date de publication:
23 Apr 2024
23 Apr 2024
Historique:
received:
12
02
2024
accepted:
17
03
2024
medline:
24
4
2024
pubmed:
24
4
2024
entrez:
24
4
2024
Statut:
aheadofprint
Résumé
Familial epilepsy with auditory features (FEAF), previously known as autosomal-dominant lateral temporal lobe epilepsy (ADLTE) is a genetically heterogeneous syndrome, clinically characterized by focal seizures with prominent auditory symptoms. It is inherited with autosomal-dominant pattern with reduced penetrance (about 70%). Sporadic epilepsy with auditory features cases are more frequent and clinically indistinguishable from familial cases. One causal gene, MICAL-1, encodes MICAL-1, an intracellular multi-domain enzyme that is an important regulator of filamentous actin (F-actin) structures. Pathogenic variants in MICAL-1 account for approximately 7% of FEAF families. Here, we describe a de novo MICAL-1 pathogenic variant, p.Arg915Cys, in a sporadic case, an affected 21-year-old Italian man with no family history of epilepsy. Genetic testing was performed in the patient and his parents, using a next-generation sequencing panel. In cell-based assay, this variant significantly increased MICAL-1 oxidoreductase activity, which likely resulted in dysregulation of F-actin organization. This finding provides further support for a gain-of-function effect underlying MICAL-1-mediated epilepsy pathogenesis, as previously seen with other pathogenic variants. Furthermore, the case study provides evidence that de novo MICAL-1 pathogenic variants can occur in sporadic cases with epilepsy with auditory feature (EAF). PLAIN LANGUAGE SUMMARY: In this study, we report a new MICAL-1 pathogenic variant in a patient without family history for epilepsy, not inherited from his parents. MICAL-1 is a protein with enzymatic activity that reorganizes the structure of the cell. We proved the pathological effect of this variant by testing its enzymatic activity and found an increase of this activity. This result suggests that non-familial cases should be tested to find novel pathogenic variants in this gene.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ricerca Corrente 2023, funds for biomedical research of the Italian Ministry of Health
Organisme : Genetic Commission of the Italian League Against Epilepsy
Organisme : Ricerca Corrente 2024, funds for biomedical research of Italian Ministry of Health
Informations de copyright
© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
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