Mutation in PHACTR1 associated with multifocal epilepsy with infantile spasms and hypsarrhythmia

0555396 - ÚMG 2022 RIV DK eng J - Journal Article
Marakhonov, A. - Přechová, Magdalena - Konovalov, F. - Filatova, A. - Zamkova, M. - Kanivets, I. - Solonichenko, V. - Semenova, N. - Zinchenko, V. V. - Treisman, R. - Skoblov, M.
Mutation in PHACTR1 associated with multifocal epilepsy with infantile spasms and hypsarrhythmia.
Clinical Genetics. Roč. 99, č. 5 (2021), s. 673-683. ISSN 0009-9163. E-ISSN 1399-0004
Institutional support: RVO:68378050
Keywords : hypsarrhythmia * malignant migrating partial seizures of infancy * multifocal epilepsy with infantile spasms * phactr1 * pp1
OECD category: Genetics and heredity (medical genetics to be 3)
Impact factor: 4.296, year: 2021
Method of publishing: Open access
https://onlinelibrary.wiley.com/doi/10.1111/cge.13926

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.
Permanent Link: http://hdl.handle.net/11104/0329917