Exome Sequencing Identified CCER2 as a Novel Candidate Gene for Moyamoya Disease

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 candidat...

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Bibliographic Details
Published in:Journal of stroke and cerebrovascular diseases 2017-01, Vol.26 (1), p.150-161
Main Authors: Mukawa, Maki, MD, Nariai, Tadashi, MD, PhD, Onda, Hideaki, MD, PhD, Yoneyama, Taku, MD, PhD, Aihara, Yasuo, MD, PhD, Hirota, Kengo, MD, Kudo, Takumi, MD, PhD, Sumita, Kazutaka, MD, PhD, Maehara, Taketoshi, MD, PhD, Kawamata, Takakazu, MD, PhD, Kasuya, Hidetoshi, MD, PhD, Akagawa, Hiroyuki, MD, PhD
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - genetics
Age of Onset
Aged
Analysis of Variance
Cardiovascular
CCER2
DNA Mutational Analysis
Exome - genetics
exome sequencing
Family Health
Female
Genetic Predisposition to Disease
Humans
Magnetic Resonance Angiography
Male
Middle Aged
Moyamoya disease
Moyamoya Disease - genetics
Neurology
susceptibility gene
Ubiquitin-Protein Ligases - genetics
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Summary: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.
ISSN:1052-3057
1532-8511
DOI:10.1016/j.jstrokecerebrovasdis.2016.09.003