PHACTR1 is associated with disease progression in Chinese Moyamoya disease.

Yongbo Yang,Yi Liu,Qun Liang,Yi Wang,Qingrong Zhang,Yichao Zhu,Chunhua Hang,Xinhua Chen,Ting Yan,Jian Wang,Shijie Na

doi:10.7717/peerj.8841

Abstract

Moyamoya disease (MMD) is a progressive stenosis at the terminal portion of internal carotid artery and frequently occurs in East Asian countries. The etiology of MMD is still largely unknown. We performed a case-control design with whole-exome sequencing analysis on 31 sporadic MMD patients and 10 normal controls with matched age and gender. Patients clinically diagnosed with MMD was determined by digital subtraction angiography (DSA). Twelve predisposing mutations on seven genes associated with the sporadic MMD patients of Chinese ancestry (CCER2, HLA-DRB1, NSD-1, PDGFRB, PHACTR1, POGLUT1, and RNF213) were identified, of which eight single nucleotide variants (SNVs) were deleterious with CADD PHRED scaled score > 15. Sanger sequencing of nine cases with disease progression and 22 stable MMD cases validated that SNV (c.13185159G>T, p.V265L) on PHACTR1 was highly associated with the disease progression of MMD. Finally, we knocked down the expression of PHACTR1 by transfection with siRNA and measured the cell survival of human coronary artery endothelial cell (HCAEC) cells. PHACTR1 silence reduced the cell survival of HCAEC cells under serum starvation cultural condition. Together, these data identify novel predisposing mutations associated with MMD and reveal a requirement for PHACTR1 in mediating cell survival of endothelial cells.

Highlights

Moyamoya disease (MMD) is a progressive stenosis at the terminal portion of internal carotid artery (ICA) with compensatory development of a hazy network of basal collaterals called Moyamoya vessels (Scott & Smith, 2009; Suzuki & Takaku, 1969)
We identified 12 predisposing mutations on seven genes associated with the sporadic MMD patients of Chinese ancestry and further validated that single nucleotide variants (SNVs) (c.13185159G>T, p.V265L) on PHACTR1 was highly associated with the disease progression of MMD
Patients with MMD determined by digital subtraction angiography (DSA) were based on the guidelines established by the Japanese Research Committee on Moyamoya disease of the Ministry of Health, Welfare and Labor, Japan (RCMJ) (Fukui, 1997)

Summary

Introduction

Moyamoya disease (MMD) is a progressive stenosis at the terminal portion of internal carotid artery (ICA) with compensatory development of a hazy network of basal collaterals called Moyamoya vessels (Scott & Smith, 2009; Suzuki & Takaku, 1969). The prevalence of MMD is the highest in East Asian countries, including Japan, Korea and China PHACTR1 is associated with disease progression in Chinese Moyamoya disease. The annual incidences of MMD in China and Japan are 0.43 and 0.54 per 100,000, which are significantly higher than that in the USA (0.086 per 100,000) and Europe (0.3 per 100,000) (Kraemer, Heienbrok & Berlit, 2008; Kuriyama et al, 2008; Miao et al, 2010; Uchino et al, 2005). Epidemiology studies had revealed several risk factors associated with MMD, such as Asian ethnicity, female gender and family history (Ganesan & Smith, 2015). The heritability of MMD is unknown, the genetic components may play an important role in the etiology of MMD (Inayama et al, 2018)

Methods

Results

Discussion

Conclusion