2. Academic Validation
  3. De novo PHACTR1 mutations in West syndrome and their pathophysiological effects

De novo PHACTR1 mutations in West syndrome and their pathophysiological effects

  • Brain. 2018 Nov 1;141(11):3098-3114. doi: 10.1093/brain/awy246.
Nanako Hamada 1 2,  Shunsuke Ogaya 3,  Mitsuko Nakashima 4,  Takuma Nishijo 5,  Yuji Sugawara 6,  Ikuko Iwamoto 1,  Hidenori Ito 1,  Yuki Maki 3,  Kentaro Shirai 7,  Shimpei Baba 8,  Koichi Maruyama 3,  Hirotomo Saitsu 9,  Mitsuhiro Kato 10,  Naomichi Matsumoto 4,  Toshihiko Momiyama 5,  Koh-Ichi Nagata 1 11
Affiliations

Affiliations

  • 1 Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya, Kasugai, Aichi, Japan.
  • 2 Research Fellow of Japan Society for the Promotion of Science, Japan.
  • 3 Department of Pediatric Neurology, Central Hospital, Aichi Human Service Center, 713-8 Kamiya, Kasugai, Aichi, Japan.
  • 4 Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Japan.
  • 5 Department of Pharmacology, Jikei University School of Medicine, 3-19-18 Nishishimbashi, Minato-ku, Tokyo, Japan.
  • 6 Department of Pediatrics, Soka Municipal Hospital, 2-21-1 Soka, Soka, Saitama, Japan.
  • 7 Department of Pediatrics, Tsuchiura Kyodo Hospital, 4-1-1 Ootsuno, Tsuchiura, Ibaraki, Japan.
  • 8 Department of Child Neurology, Comprehensive Epilepsy Center, Seirei-Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Naka-ku, Hamamatsu, Shizuoka, Japan.
  • 9 Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Japan.
  • 10 Department of Pediatrics, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan.
  • 11 Department of Neurochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.
PMID: 30256902 DOI: 10.1093/brain/awy246
Abstract

Trio-based whole exome Sequencing identified two de novo heterozygous missense mutations [c.1449T > C/p.(Leu500Pro) and c.1436A > T/p.(Asn479Ile)] in PHACTR1, encoding a molecule critical for the regulation of protein Phosphatase 1 (PP1) and the actin Cytoskeleton, in unrelated Japanese individuals with West syndrome (infantile spasms with intellectual disability). We then examined the role of Phactr1 in the development of mouse cerebral cortex and the pathophysiological significance of these two mutations and Others [c.1561C > T/p.(Arg521Cys) and c.1553T > A/p.(Ile518Asn)], which had been reported in undiagnosed patients with intellectual disability. Immunoprecipitation analyses revealed that actin-binding activity of PHACTR1 was impaired by the p.Leu500Pro, p.Asn479Ile and p.Ile518Asn mutations while the p.Arg521Cys mutation exhibited impaired binding to PP1. Acute knockdown of mouse Phactr1 using in utero electroporation caused defects in cortical neuron migration during corticogenesis, which were rescued by an RNAi-resistant PHACTR1 but not by the four mutants. Experiments using knockdown combined with expression mutants, aimed to mimic the effects of the heterozygous mutations under conditions of haploinsufficiency, suggested a dominant negative effect of the mutant allele. As for dendritic development in vivo, only the p.Arg521Cys mutant was determined to have dominant negative effects, because the three other mutants appeared to be degraded with these experimental conditions. Electrophysiological analyses revealed abnormal synaptic properties in Phactr1-deficient excitatory cortical neurons. Our data show that the PHACTR1 mutations may cause morphological and functional defects in cortical neurons during brain development, which is likely to be related to the pathophysiology of West syndrome and other neurodevelopmental disorders.

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