Genetic analysis of RNF213 p.R4810K variant in non-moyamoya intracranial artery stenosis/occlusion disease in a Chinese population
Zhang et al. Environmental Health and Preventive Medicine
Genetic analysis of RNF213 p.R4810K variant in non-moyamoya intracranial artery stenosis/occlusion disease in a Chinese population
Tong Zhang 2
Congrong Guo 1
Xin Liao 0
Jian Xia 3
XiaoXiao Wang 2
Jing Deng 0
Junxia Yan 0
0 Department of Epidemiology and Health Statistics, XiangYa School of Public Health, Central South University , Shang Mayuanling, KaiFu District, Changsha 410078 , China
1 Department of Ophthalmology, the Second Hospital of Hebei Medical University , Heping West Road, Xinhua District, Shijiazhuang 050000 , China
2 Department of Neurology, the Second Hospital of Hebei Medical University , Heping West Road, Xinhua District, Shijiazhuang 050000 , China
3 Department of Neurology, XiangYa Hospital, Central South University , 87 Xiangya Road, Changsha, Hunan 410008 , China
Objectives: RNF213 p.R4810K was identified as a susceptibility variant for moyamoya disease in Asia and non-moyamoya intracranial artery stenosis/occlusion disease in Japan and Korea recently. The occurrence of this variant was evaluated in patients with non-moyamoya intracranial artery stenosis/occlusion disease in China. Methods: Two study populations were used in this study. One was recruited from the Second Hospital of Hebei Medical University from April 2015 to May 2016. The other was the archived DNA samples of intracranial artery stenosis/occlusion patients in XiangYa Hospital collected in 2014. The occurrence of RNF213 p.R4810K was investigated in a total of 715 patients with non-moyamoya intracranial artery stenosis/occlusion disease. The carrier rate of RNF213 p.R4810K in 507 normal individuals was used as control. Results: Six of 715 patients (0.84%) with non-moyamoya intracranial artery stenosis/occlusion disease and 2 of the 507 normal controls (0.39%) had RNF213 p.R4810K variant. The carrier rate of RNF213 p.R4810K was higher in non-moyamoya intracranial artery stenosis/occlusion group than that in the normal group. However, no statistically significant association was observed (Odds ratio, 2.14; 95% confidence interval, 0.43-10.63; p = 0.56). Conclusions: The carrier rate of RNF213 p.R4810K in Chinese non-moyamoya intracranial artery stenosis/occlusion disease patients was significantly lower than that in Korea or Japan. Genetic heterogeneity was highly indicated. Further systematic genetic epidemiology studies with emphasis on Chinese-specific genetic variants and environmental risk factors of intracranial artery stenosis/occlusion disease in larger population are needed.
Intracranial artery stenosis/occlusion disease; Genetics; RNF213; p; R4810K; China
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Introduction
The ring finger protein 213 (RNF213) was identified as a
susceptibility gene for moyamoya disease (MMD) recently
[1, 2]. Several studies revealed high frequencies of the
same RNF213 variant- p.R4810K (rs112735431, GenBank
accession number AB537889) in East Asian MMD
patients compared to normal controls (ORs > 100), which
was illustrated as a founder mutation in Japanese, Korean
and Chinese patients [1–9]. Indeed, in Japan and Korea,
the majority (~80%) of MMD patients carried at least one
allele of RNF213 p.R4810K, which was significantly higher
than that in the general population [1, 2, 4–6, 8–16]. In
China, the carrier rate of RNF213 p.R4810K in MMD
patients was about 20% [1, 3, 17–19]. MMD risk was highly
increased by this variant in the Asian population.
RNF213 located in chromosome 17q25.3, encoding a
596 kDa protein which functions both as an AAA‑type
ATPase and an E3 ligase [20]. AAA-ATPases mediate
various cell functions, including membrane
fusion/transport, proteolysis, protein disaggregation/refolding, DNA
recombination/repair and mitosis/meiosis [21]. AAA-ATPase
dysfunction can cause several diseases, such as PEX1/PEX6
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mutations cause multiple organ degeneration [22, 23] and
Cdc48 mutations cause amyotrophic lateral sclerosis
[24, 25]. E3 ligase activity may play a role in protein
degradation or signaling processes [1]. Even the complete
physiological functions of RNF213 are still unknown,
knockdown of RNF213 in zebrafish leads to abnormal
sprouting and irregular diameter of intracranial vessels,
suggesting some contribution to vascular formation [1].
Previous studies revealed that a wide spectrum of
phenotypes could occur within a family unit despite the
members having the i (...truncated)