title: Exome Sequencing Identified CCER2 as a Novel Candidate Gene for Moyamoya Disease.
abstract: The etiology of Moyamoya disease (MMD) is still largely unclear, despite identification of RNF213 as the most significant susceptibility gene in East Asian patients. Following up our previous study confirming genetic heterogeneity in Japanese patients with MMD, we extensively surveyed novel candidate genes for a new perspective on the etiology of this disease. Two characteristic pedigrees without susceptibility variants in RNF213 were selected for whole-exome sequencing; 1 harbored 3 affected members, and the other included discordant monozygotic twins. In the former pedigree, 12 rare mutations in 12 genes were co-segregated with MMD. One of the most deleterious amino acid changes among these was p.T76_G80delinsPS in CCER2, which was also mutated in the latter pedigree (p.E242K), although the unaffected twin sister shared the same mutation reflecting reduced penetrance. These CCER2 mutations were predicted to promote aggregation or oligomerization of their protein product, using in silico functional analysis. Subsequent CCER2 re-sequencing in an additional 135 MMD probands identified 1 recurrent and an additional 2 in-frame insertion-deletion mutations, recurrent p.T76_G80delinsPS, p.H218_H220del, and p.E299del. Although CCER2 molecular function is not well characterized, it is a secretory protein expressed in the brain; therefore, it constitutes a potential biomarker of MMD.
authors.affiliation: Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Mukawa
authors.affiliation: Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nariai
authors.affiliation: Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan; Department of Neurosurgery, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Onda
authors.affiliation: Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan; Department of Neurosurgery, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Yoneyama
authors.affiliation: Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Aihara
authors.affiliation: Department of Neurosurgery, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Hirota
authors.affiliation: Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kudo
authors.affiliation: Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Sumita
authors.affiliation: Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Maehara
authors.affiliation: Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Takakazu
authors.initials: T
authors.lastname: Kawamata
authors.affiliation: Department of Neurosurgery, Tokyo Women's Medical University Medical Center East, Tokyo, Japan; Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS), Tokyo, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kasuya
authors.affiliation: Department of Neurosurgery, Tokyo Women's Medical University Medical Center East, Tokyo, Japan; Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS), Tokyo, Japan. Electronic address: akagawa.hiroyuki@twmu.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Akagawa
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D017668:Age of Onset; D000368:Aged; D000704:Analysis of Variance; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D018810:Magnetic Resonance Angiography; D008297:Male; D008875:Middle Aged; D009072:Moyamoya Disease / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C557998:RNF213 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases
keywords: CCER2; Moyamoya disease; exome sequencing; susceptibility gene