Mutation in PHACTR1 associated with multifocal epilepsy with infantile spasms and hypsarrhythmia. Issue 5 (27th January 2021)

• Record Type: Journal Article
• Authors: Marakhonov, Andrey V.; Přechová, Magdalena; Konovalov, Fedor A.; Filatova, Alexandra Yu.; Zamkova, Maria A.; Kanivets, Ilya V.; Solonichenko, Vladimir G.; Semenova, Natalia A.; Zinchenko, Rena A.; Treisman, Richard; Skoblov, Mikhail Yu.
• Is Part Of: Clinical genetics. Volume 99:Issue 5(2021)
• Page Start: 673
• Page End: 683
• Publication Date: 2021-01-27
• Subjects: hypsarrhythmia -- malignant migrating partial seizures of infancy -- multifocal epilepsy with infantile spasms -- PHACTR1 -- PP1; Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.13926
• Languages: English
• ISSNs: 0009-9163

Abstract

Abstract: 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. Abstract : 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.