2. Academic Validation
  3. Biallelic Variants in CNPY3, Encoding an Endoplasmic Reticulum Chaperone, Cause Early-Onset Epileptic Encephalopathy

Biallelic Variants in CNPY3, Encoding an Endoplasmic Reticulum Chaperone, Cause Early-Onset Epileptic Encephalopathy

  • Am J Hum Genet. 2018 Feb 1;102(2):321-329. doi: 10.1016/j.ajhg.2018.01.004.
Hiroki Mutoh 1,  Mitsuhiro Kato 2,  Tenpei Akita 1,  Takuma Shibata 3,  Hiroyuki Wakamoto 4,  Hiroko Ikeda 5,  Hiroki Kitaura 6,  Kazushi Aoto 7,  Mitsuko Nakashima 7,  Tianying Wang 1,  Chihiro Ohba 8,  Satoko Miyatake 8,  Noriko Miyake 8,  Akiyoshi Kakita 6,  Kensuke Miyake 3,  Atsuo Fukuda 1,  Naomichi Matsumoto 9,  Hirotomo Saitsu 10
Affiliations

Affiliations

  • 1 Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
  • 2 Department of Pediatrics, Showa University School of Medicine, Tokyo 142-8666, Japan.
  • 3 Division of Infectious Genetics, Department of Microbiology and Immunology, University of Tokyo, Tokyo 108-8639, Japan.
  • 4 Department of Pediatrics, Ehime Rehabilitation Center for Children, Ehime 791-0212, Japan.
  • 5 Department of Pediatrics, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, National Hospital Organization, Shizuoka 420-8688, Japan.
  • 6 Department of Pathology, Brain Research Institute, University of Niigata, Niigata 951-8585, Japan.
  • 7 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
  • 8 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
  • 9 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address: [email protected].
  • 10 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan. Electronic address: [email protected].
PMID: 29394991 DOI: 10.1016/j.ajhg.2018.01.004
Abstract

Early-onset epileptic encephalopathies, including West syndrome (WS), are a group of neurological disorders characterized by developmental impairments and intractable seizures from early infancy. We have now identified biallelic CNPY3 variants in three individuals with WS; these include compound-heterozygous missense and frameshift variants in a family with two affected siblings (individuals 1 and 2) and a homozygous splicing variant in a consanguineous family (individual 3). All three individuals showed hippocampal malrotation. In individuals 1 and 2, electroencephalography (EEG) revealed characteristic fast waves and diffuse sharp- and slow-wave complexes. The fast waves were clinically associated with seizures. CNPY3 encodes a co-chaperone in the endoplasmic reticulum and regulates the subcellular distribution and responses of multiple Toll-like receptors. The amount of CNPY3 in lymphoblastoid cells derived from individuals 1 and 2 was severely lower than that in control cells. Cnpy3-knockout mice exhibited spastic or dystonic features under resting conditions and hyperactivity and anxiolytic behavior during the open field test. Also, their resting EEG showed enhanced activity in the fast beta frequency band (20-35 Hz), which could mimic the fast waves in individuals 1 and 2. These data suggest that CNPY3 and Cnpy3 perform essential roles in brain function in addition to known Toll-like receptor-dependent immune responses.

Keywords

CNPY3; PRAT4A; Toll-like receptor; West syndrome; chaperone; early-onset epileptic encephalopathy; fast waves; hippocampal malrotation.

Figures