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.

Independent Clinical Bioinformatics Laboratory Moscow Russia

Laboratory of Genetic Epidemiology Laboratory of Functional Genomics Department of Genetic Counseling Research Centre for Medical Genetics Moscow Russia

Laboratory of Integrative Biology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Molecular Pathology Genomed Ltd Moscow Russia

Laboratory of Regulatory Mechanisms in Immunity Institute of Carcinogenesis N N Blokhin Russian Cancer Research Center Moscow Russia

Medical Genetic Centre Filatov Moscow Pediatric Clinical Hospital Moscow Russia

N A Semashko National Research Institute of Public Health Moscow Russia

Signalling and Transcription Laboratory Francis Crick Institute London UK

Citace poskytuje Crossref.org