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Mutation in PHACTR1 associated with multifocal epilepsy with infantile spasms and hypsarrhythmia
Clinical Genetics ( IF 2.9 ) Pub Date : 2021-01-19 , DOI: 10.1111/cge.13926 Andrey V Marakhonov 1 , Magdalena Přechová 2, 3 , Fedor A Konovalov 4 , Alexandra Yu Filatova 1 , Maria A Zamkova 5 , Ilya V Kanivets 6, 7 , Vladimir G Solonichenko 7 , Natalia A Semenova 1 , Rena A Zinchenko 1, 8 , Richard Treisman 3 , Mikhail Yu Skoblov 1
Clinical Genetics ( IF 2.9 ) Pub Date : 2021-01-19 , DOI: 10.1111/cge.13926 Andrey V Marakhonov 1 , Magdalena Přechová 2, 3 , Fedor A Konovalov 4 , Alexandra Yu Filatova 1 , Maria A Zamkova 5 , Ilya V Kanivets 6, 7 , Vladimir G Solonichenko 7 , Natalia A Semenova 1 , Rena A Zinchenko 1, 8 , Richard Treisman 3 , Mikhail Yu Skoblov 1
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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.
中文翻译：
PHACTR1 突变与多灶性癫痫伴婴儿痉挛和高节律失常相关
一名患有多灶性癫痫的小男孩，伴有婴儿痉挛和高节律失常，脑结构的器质性病变极少，接受了全外显子组测序的 DNA 诊断。鉴定了PHACTR1基因中的杂合氨基酸取代 p.L519R 。PHACTR1 属于 G-肌动蛋白结合蛋白磷酸酶 1 (PP1) 辅助因子的蛋白质家族，以前与人类疾病无关。先证者中的错义单核苷酸变体显示在父系等位基因中从头发生。该突变在体外显示降低 PHACTR1 对 G-actin 的亲和力，并增加其与 PP1 催化亚基形成复合物的倾向。这些特性与 PHACTR1 的亚细胞定位改变和诱导细胞骨架重排的能力增加有关。尽管 PHACTR1 在神经元兴奋性和分化中的分子作用仍有待确定，但 PHACTR1 先前已被证明与 Slack 通道病发病机制有关，这与我们的研究结果一致。我们得出结论，PHACTR1 中的这种激活突变会导致患者出现严重类型的散发性多灶性癫痫。
更新日期：2021-01-19
中文翻译：
PHACTR1 突变与多灶性癫痫伴婴儿痉挛和高节律失常相关
一名患有多灶性癫痫的小男孩，伴有婴儿痉挛和高节律失常，脑结构的器质性病变极少，接受了全外显子组测序的 DNA 诊断。鉴定了PHACTR1基因中的杂合氨基酸取代 p.L519R 。PHACTR1 属于 G-肌动蛋白结合蛋白磷酸酶 1 (PP1) 辅助因子的蛋白质家族，以前与人类疾病无关。先证者中的错义单核苷酸变体显示在父系等位基因中从头发生。该突变在体外显示降低 PHACTR1 对 G-actin 的亲和力，并增加其与 PP1 催化亚基形成复合物的倾向。这些特性与 PHACTR1 的亚细胞定位改变和诱导细胞骨架重排的能力增加有关。尽管 PHACTR1 在神经元兴奋性和分化中的分子作用仍有待确定，但 PHACTR1 先前已被证明与 Slack 通道病发病机制有关，这与我们的研究结果一致。我们得出结论，PHACTR1 中的这种激活突变会导致患者出现严重类型的散发性多灶性癫痫。
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