Mutation in PHACTR1 associated with multifocal epilepsy with infantile spasms and hypsarrhythmia
| Autor: | Rena A. Zinchenko, Alexandra Filatova, Vladimir G. Solonichenko, Andrey V. Marakhonov, Ilya V. Kanivets, Magdalena Přechová, Richard Treisman, Natalia A. Semenova, F. A. Konovalov, Mikhail Skoblov, Maria A. Zamkova |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Proband Male hypsarrhythmia 030105 genetics & heredity Biology multifocal epilepsy with infantile spasms medicine.disease_cause Pathogenesis 03 medical and health sciences Epilepsy Mice Channelopathy Exome Sequencing Genetics medicine Missense mutation Animals Humans Allele Genetics (clinical) Mutation malignant migrating partial seizures of infancy PHACTR1 Microfilament Proteins Infant Original Articles medicine.disease PP1 Hypsarrhythmia Actins 030104 developmental biology Child Preschool Cancer research NIH 3T3 Cells Original Article medicine.symptom Spasms Infantile |
| Zdroj: | Clinical Genetics |
| ISSN: | 1399-0004 0009-9163 |
| Popis: | A young boy with multifocal epilepsy with infantile spasms and hypsarrhythmia with minimal organic lesions of brain structures underwent DNA diagnosis using whole‐exome sequencing. A heterozygous amino‐acid substitution p.L519R in a PHACTR1 gene was identified. PHACTR1 belongs to a protein family of G‐actin binding protein phosphatase 1 (PP1) cofactors and was not previously associated with a human disease. The missense single nucleotide variant in the proband was shown to occur de novo in the paternal allele. The mutation was shown in vitro to reduce the affinity of PHACTR1 for G‐actin, and to increase its propensity to form complexes with the catalytic subunit of PP1. These properties are associated with altered subcellular localization of PHACTR1 and increased ability to induce cytoskeletal rearrangements. Although the molecular role of the PHACTR1 in neuronal excitability and differentiation remains to be defined, PHACTR1 has been previously shown to be involved in Slack channelopathy pathogenesis, consistent with our findings. We conclude that this activating mutation in PHACTR1 causes a severe type of sporadic multifocal epilepsy in the patient. Activating nature of the PHACTR1 L519R mutation. Left, PHACTR1 binds multiple G‐actin molecules (shown symbolically by a single red circle) which antagonise formation of the PHACTR1/PP1 complex, which will therefore form only when local G‐actin concentration falls below a threshold. Right, PHACTR1 L519R (star) exhibits reduced G‐actin binding affinity, allowing the PHACTR1/PP1 complex to form at higher G‐actin concentation. The L519R mutation affects PHACTR1 subcellular localisation as well, and it is therefore possible that its phenotype additionally reflects redistribution of PP1. |
| Databáze: | OpenAIRE |
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