SLC2A3 variants in familial and sporadic congenital heart diseases in a Chinese Yunnan population

BackgroundSolute carrier family 2 member 3 (SLC2A3), is a member of a superfamily of transport protein genes. SLC2A3 played an important role in embryonic development. Previous research reported SLC2A3 duplication was reportedly associated with congenital syndromic heart defects. However, it is not clear whether the gene is associated with non‐syndromic congenital heart disease. Our study aimed to elucidate the relationship between its variation and congenital heart disease.MethodsGenomic DNA extracted from the peripheral blood leukocytes of two families with CHD were sequenced with whole‐exome sequencing to identify variations, used Sanger sequencing to investigate SLC2A3 variants in 494 Chinese patients with CHD and 576 healthy unrelated individuals.ResultsIn members from the two families, three with CHD had the SLC2A3 (rs3931701) C > T variant. Of the 494 patients with CHD, 394 had gene variants (86 had the TT type and 308 had the CT type). Of the 576 healthy controls, 272 participants had gene variants (36 had the TT type and 236 had the CT type). The TT type [p < 0.0001, odds ratio (OR) =7.262, 95% confidence interval (CI) =4.631–11.388] and CT type (p < 0.0001, OR =3.967, 95% CI =2.991–5.263) of SLC2A3 (rs3931701) significantly increased the risk of sporadic ASD in a Chinese Yunnan population.ConclusionsSingle nucleotide variations of SLC2A3, particularly, the SLC2A3 (rs3931701) C > T variant increased the risk of CHD among the studied population.     

How Can We Identify Very High-Risk Heterozygous Familial Hypercholesterolemia?

Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder that elevates low-density lipoprotein cholesterol and increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). However, despite their atherogenic lipid profiles, the cardiovascular risk of HeFH varies in each individual. Their variety of phenotypic features suggests the need for better risk stratification to optimize their therapeutic management. The current review summarizes three potential approaches, including (1) definition of familial hypercholesterolemia (FH)-related risk scores, (2) genetic analysis, and (3) biomarkers. The International Atherosclerosis Society has recently proposed a definition of severe FH to identify very high-risk HeFH subjects according to their clinical characteristics. Furthermore, published studies have shown the association of FH-related genetic phenotypes with ASCVD, which indicates the genetic analysis’s potential to evaluate individual cardiovascular risks. Biomarkers reflecting disease activity have been considered to predict the formation of atherosclerosis and the occurrence of ASCVD in HeFH subjects. Incorporating these risk stratifications will be expected to allocate adequate intensity of lipid-lowering therapies in HeFH subjects, which ultimately improves cardiovascular outcomes.     

The FLT3 Y842D mutation may be highly sensitive to midostaurin: a case report

A Y842D mutation within the activation loop of fms-like tyrosine kinase 3 (FLT3) has been shown to confer strong resistance to sorafenib in vitro. Whether this type of mutation exerts clinically significant effects in patients with acute myeloid leukaemia (AML) remains unclear. Here, a novel Y842D activating mutation within the kinase domain of FLT3, in a pregnant patient with de novo hyperleucocyte acute myeloid leukaemia, is described. Following induction failure with standard dose idarubicin and cytarabine (IA), the patient received re-induction combined with midostaurin, a promising agent targeting mutant-FLT3, and IA regimen. Fortunately, morphological remission was achieved. During the period of midostaurin treatment, the patient exhibited a symptom that was characteristic of differentiation syndrome, which disappeared following treatment with methylprednisolone. The present case revealed that Y842D, an uncommon activating mutation in the activation loop of FLT3, may be a midostaurin-sensitive mutation type in patients with acute myeloid leukaemia.     

Repeated Necrotizing Lymphadenitis with MEFV Gene Mutations

We herein report a 36-year-old man with repeated necrotizing lymphadenitis due to MEFV gene mutations. The patient''s chief complaints were a fever and painful cervical lymphadenopathy. We diagnosed him with necrotizing lymphadenitis based on the pathological findings of the lymph nodes and the exclusion of other differential diseases. The same episode recurred four times. We speculated the involvement of autoinflammatory backgrounds and detected MEFV gene mutations of E148Q (homo), P369S, and R408Q. Considering the elevation of interleukin-18, these mutations probably played roles in the repeated necrotizing lymphadenitis.     

iTRAQ串联质谱筛选尾吊小鼠感染空间诱变大肠杆菌后脾脏差异表达蛋白

目的应用同重同位素标记相对与绝对定量技术(iTRAQ),联合液相色谱串联质谱(LC-MS/MS),检测经空间诱变大肠杆菌(T1-13)感染尾吊模拟失重小鼠后,其脾脏组织中的差异蛋白,并探讨其生物学意义。方法 C57BL/6小鼠尾吊模拟失重后以空间诱变大肠杆菌灌胃建立感染模型,采用iTRAQ结合LC-MS/MS技术筛选脾脏组织差异表达蛋白,并对差异蛋白进行GO、pathway富集分析和STRING蛋白互作分析。结果共鉴定出2589个蛋白,尾吊组与对照组相比筛选出378个差异表达蛋白。尾吊染菌后与对照组相比,共筛选出452个差异表达蛋白,STRING蛋白互作网络中有286个差异蛋白间存在相互作用,这些差异蛋白经KEGG分析共得到32条存在显著性的通路,主要为氧化磷酸化通路,代谢通路、蛋白消化和吸收通路、蛋白酶体通路。结论成功筛选出了模拟失重后空间诱变大肠杆菌感染脾脏组织差异表达蛋白,这些差异蛋白可能通过调控代谢通路、不同环境下微生物代谢、颉氨酸/亮氨酸/异亮氨酸降解、溶酶体、碳代谢、吞噬体、丙酸代谢、蛋白酶体参与失重条件下免疫和炎症反应的发生。     

中国人2型糖尿病合并高甘油三酯血症患者脂蛋白酯酶基因突变及功能分析

目的 研究中国人2型糖尿病合并高甘油三酯血症患者脂蛋白醒酶(1ipoprotein lipase,LPL)基因突变及对酶功能的影响,从脂代谢途径探讨引发糖尿病的遗传因素。方法 对高甘油三酯及血脂正常的2型糖尿病患者和正常人的LPL基因进行研究。利用PCR—SSCP、PCR—RFLP及DNA测序技术对LPL基因的启动子和10个外显子区域进行突变检测,针对特异位点进行体外定点突变和酶活力表达研究,利用网上工具平台Swiss-PDB Viewer对正常和突变蛋白进行二级结构模拟分析。结果 在177例高甘油三酯2型糖尿病患者中检测到4种错义突变：Ala71Thr、Val181IIe、Glyl88Glu和Glu242Lys,在正常血脂的糖尿病患者和健康人组中没有检出以上突变。这4种突变位于进化上高度保守的氨基酸位点,并分别在高度保守的外显子3、5及6区域。体内和体外酶活力研究表明,这4个突变均引起了酶活力降低甚至失活,其改变程度可以从它们所在序列的保守性、在酶功能结构城中的相对位置、相应的二级结构改变和氨基酸特性获得解释。结论 在受累个体中,LPL突变是引起患者血浆甘油三酯升高的直接原因,是其发展成2型糖尿病的遗传性易感因素。     

Effect of chinese medicine therapy for strengthening-Pi and nourishing-shen in preventing lamivudine induced YMDD mutation and its immunologic mechanism

<正>Objective:To observe the effect of Chinese medicine therapy for strengthening-Pi(脾) and nourishing-Shen(肾,SPNS) in preventing lamivudine induced YMDD mutation and its immunological mechanism.Methods:One hundred and sixty chronic hepatitis B(CHB) patients with positive HBeAg were equally assigned to two groups at random:the observation group and the control group.Patients in the observation group were treated with lamivudine combined with SPNS,and those in the control group were treated with lamivudine only,with the treatment lasting for 52 weeks in total.Changes in indexes,including liver function,HbeAg,HBV-DNA,YMDD variation,CD_4,CD_4/CD_8 ratio,interferon-γ(IFN-γ),interleukin-4(IL-4), blood routine,renal function,as well as any adverse reactions that occurred in patients,were observed at different time points.Results:The ALT,AST recovery rate and HBV-DNA negatively inversing rate at the 24th week,the 36th week and the 52nd week were all higher(P0.05);meanwhile,the YMDD mutation rate at the 36th week and the 52nd week was lower(P0.05) in the observation group than in the control group.The posttreatment levels of CD_4,CD_4/CD_8 ratio,IFN-γ,and IL-4 as well as the pre-post treatment difference of these indexes in the observation group were significantly different from those in the control group(P0.05).Conclusion: Chinese medicine SPNS therapy can significantly reduce the YMDD variation of HBV,and the mechanism may be related to its regulation of the CD_4 level,CD_4/CD_8 ratio and Th1/Th2 balance.     

野生型人LPL及联合突变体原核表达载体构建及抗体制备

目的构建野生型人脂蛋白脂酶(LPL)和联合突变体的pET28a( )原核表达载体,蛋白纯化后制备突变型多克隆抗体。方法采用RT-PCR技术从人肾周脂肪组织中获得野生型LPLcDNA,酶切和测序鉴定后插入原核表达载体pET28a( ),通过两次定点诱变得到pET28a( )-Asn291Ser和Lys312inC联合突变LPL,酶切和测序鉴定后分别转染大肠杆菌BL21。异丙基-β-D-硫代半乳糖苷(IPTG)诱导,SDS-PAGE电泳分析;镍柱亲和层析纯化,Western blotting鉴定;将纯化后的突变型LPL蛋白免疫新西兰大白兔,Western blotting检测血清突变型多克隆抗体滴度。结果经酶切和测序鉴定,所构建的野生型LPL及联合突变LPL的基因片段正确;两种重组质粒转染大肠杆菌BL21后,均呈高效表达;SDS-PAGE电泳分析及Western blotting鉴定表明,诱导纯化后的蛋白为目的蛋白;兔抗突变型LPL的多克隆抗体滴度达1∶100000。结论成功构建pET28a( )-野生型LPL及pET28a( )-Asn291Ser和Lys312inC联合突变LPL,同时利用获得的高纯度蛋白制备了高效价突变型LPL多克隆抗体,为进一步进行野生型LPL和突变型LPL蛋白的体内试验奠定了基础。     

乳腺癌易患基因1、2基因突变的研究进展

乳腺癌作为女性常见恶性肿瘤之一,近年来,在国内外发病率逐年上升,且越发年轻化。在乳腺癌患者中,一部分表现出家族聚集性、发病早,且累及家系中多个成员。乳腺癌易患基因1、2(BRCA1、2)是乳腺癌遗传性易患基因。有研究证实,BRCA1、2基因参与乳腺癌的发生、发展过程,并在其中扮演重要角色。该文对国内外乳腺癌BRCA基因突变研究现状进行总结,并就BRCA基因突变在乳腺癌防治和预后方面的研究进展予以综述。