COSMC mutations reduce T-synthase activity in advanced Alzheimer's disease
COSMC mutations reduce T-synthase activity in advanced Alzheimer's disease
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DOI：
10.1002/trc2.12040
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发表时间：
2020-01-01
影响因子：
4.8
通讯作者：
Lalezari, Parviz
中科院分区：
文献类型：
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作者：
Gollamudi, Seema;Lekhraj, Rukmani;Lalezari, Parviz
简介：随着年龄的增长，脑组织中积累的突变可能会导致阿尔茨海默病(AD)。AD患者存在糖蛋白和TN抗原表达异常。我们在AD和年龄匹配的正常人中发现了CIGALT1C1/Cosmc突变。方法：通过对COSMc基因突变的鉴定、实时定量逆转录聚合酶链式反应(Q-RT-PCR)、免疫印迹和T-合成酶活性检测。结果：在AD患者和正常对照组中，COSMC基因的启动子、编码区和3‘端非编码区均存在COSMC突变。COSMC编码突变与AD进展相关。进展期AD患者的T-合成酶水平显著高于AD III(P=0.03)和正常对照组(P=0.002)。有Cosmc编码突变的晚期AD(Braak和Braak(B&B)期V和VI期)的T-合酶活性比无突变的晚期AD低3倍，比正常(P=0.001)和有编码突变的AD B&B期III(P=0.01)低1.3倍。
Introduction: Mutations in brain tissues that cumulate with age may contribute to Alzheimer's disease (AD). Abnormal glycoprotein and Tn antigen expression have been demonstrated in AD. We identified CIGALT1C1/COSMC mutations in AD and age-matched normals without AD. The COSMC coding mutations resulted in a significant reduction in T-synthase activity in advanced AD cases.Methods: Identification of COSMC mutations, Real Time Quantitative Reverse Transcription PCR (Q-RT-PCR), western blotting, and T-synthase activity assays.Results: COSMC mutations were detected in the promotor, coding region and 3'UTR in AD and normals. COSMC coding mutations demonstrated a correlation with AD progression. T-synthase levels were significantly elevated in advanced AD compared to AD III (P = 0.03) and normals (P = 0.002). T-synthase activity in advanced AD (Braak and Braak (B&B) stages V and VI) with COSMC coding mutations was 3-fold lower than advanced AD without mutations, and 1.3-fold lower than normal (P = 0.001) and AD B&B stage III (P = 0.01) with coding mutations.Discussion: COSMC coding mutations significantly diminished T-synthase activity in advanced AD, potentially causing defective galactosylation.