FMRP蛋白参与DNA损伤应答

脆性X综合征是世界范围内最常见的遗传性智力缺陷,由脆性X智障蛋白（fragile X mental retardationprotein,FMRP）功能缺陷导致,但目前对其致病机制所知甚少。中国科学院遗传与发育生物学研究所张永清研究小组和大连医科大学肿瘤干细胞研究员秘晓林研究团队密切合作,发现了FMRP参与调节DNA损伤应答的机制。     

脆性X综合征诊断及出生前诊断

目的探讨脆性X综合征诊断及出生前诊断方法。方法建立低叶酸双诱导双定位方法和基因诊断方法对弱智、癫痫加弱智、智力低下及其亲属及产前诊断共1326例。结果发现外周血1318例,脆性X染色体阳性148例,经过家系调查9个大的家系(超过3个患者/家系);基因产前诊断4例阳性,脆性X染色体阳性共152例,检出率占11.46%。结论低叶酸双诱导双定位方法结合基因诊断方法脆性X综合征和产前诊断,提高诊断率。     

兄弟俩Fra（X）综合征家系及PCR诊断

脆性X染色体综合征（Fra（X）综合征）是仅次于DOWN综合征的家庭性、智力低下性疾病之一。我们对1992年9月在智力低下门诊发现的兄弟俩Fra（X）综合征患者（均经上海医科大学遗传医学研究室检查确诊）的一家三代6个人用聚合酶链反应（PCR）方法检测该家系的FMR－1基因，现报告如下。临床资料一、资料来源正常对照：无智力低下的普通门诊病人15例，男6例，女9例。Fra（X）综合征家系：兄弟俩、父母亲、外祖父、外祖母。兄弟俩均经细胞遗传检查确诊，母亲细胞遗传学检查正常，父亲、外祖父、外祖母来经细胞遗传学检查。兄弟均有典型的…     

脆性X综合征三例家系分析

脆性X综合征（fragile X chromosome，FraX）是由于X染色体畸变导致的以智能低下为主要表现的染色体病。本文就脆性X综合征的临床特点、细胞遗传学特征以及遗传规律进行分析，以期为临床上早期诊断、遗传咨询和生殖干预提供参考依据。     

SARS患者外周血中T淋巴细胞亚群变化及其临床意义

目的 了解SARS患者外周血T淋巴细胞亚群的变化规律及其临床意义。方法 采用免疫细胞化学方法对12例临床确诊SARS患者和20例健康献血员外周血淋巴细胞亚群进行检测。结果12例患者外周血CD~ 、CD_4~ 和CD_8~ 细胞的百分率均较对照组明显降低(P值均<0.05),其中CD_4~ 细胞下降幅度最大;CD_4~ 细胞减少与淋巴细胞降低的关联性最明显(r=0.679,P<0.05)。结论 SARS患者细胞免疫功能存在明显损伤,临床应用糖皮质激素宜严格掌握指征。     

智低人群中脆性X综合征的细胞,分子遗传学研究

采用ＰＣＲ、ＳｏｕｔｈｅｒｎＢｌｏｔ印迹杂交及细胞遗传学方法，对２３３名原性智力低下患儿进行了ＦＭＲ－１基因的突变分析和Ｘｑ２７．３脆性位点检查。结果：确诊９名脆性Ｘ综合征患者，占３．８６％，并在部分家庭成员中检出了女性前突变和全突变携带者，排除细胞学方法假阳性１例。     

一种经济的脆性X综合征的PCR检测法

目的建立一种经济的用于脆性x综合征临床大面积筛查的简便的检测方法。方法同时用加入betaine作为PCR增强剂的扩增体系和用PfxAmpTaq酶Enhance扩增体系检测脆性x综合征（FraX）FMR-1基因，检N（CGG）n重复数的多少，对脆性x综合征可疑病人进行筛查。结果扩增目的片段为237—372bp，样本未见扩增片段的为脆性x综合征患者。样本可见明显扩增片段的为正常人。在不明原因的智力低下的儿童中筛查出3例脆性x综合征患者。两种方法对FMR-1基因的CGG重复序列扩增效果均较好。结论用加入betaine扩增体系更经济可应用于临床大批量的标本筛查。     

原发性肾病综合征患儿CD4+CD2 5+调节性T细胞的变化及临床意义

目的 探讨原发性肾病综合征(PNS)患儿外周血淋巴细胞亚群及CD4+CD25+调节性T细胞的变化及其临床意义.方法 采用流式细胞术检测23例PNS(肾病组)患儿外周血T淋巴细胞亚群,同时检测17例健康儿童作为对照组.结果 PNS患儿外周血中CD4+CD25+淋巴细胞较正常对照组明显升高(P＜0.05).结论 体内异常的CD4+CD25+调节性T细胞水平参与了PNS的发病过程.PNS患儿存在细胞免疫功能紊乱,纠正或调节细胞免疫功能可应用于PNS的临床治疗.     

急性乙型肝炎外周血淋巴细胞亚群动态分析

目的 探讨急性乙型肝炎(AHB)患者外周血免疫细胞包括T淋巴细胞亚群、B淋巴细胞和自然杀伤(NK)细胞在疾病发展中的动态变化及其意义.方法 流式细胞技术检测17例AHB患者(AHB组)外周血淋巴细胞亚群动态变化和36例慢性乙型肝炎(CHB组)患者及32例正常对照组淋巴细胞亚群分布特点;动态检测AHB患者CD4~+/CD8~+变化,并探讨其与ALT改变及与HBVDNA清除的相关性.结果 AHB组人院4周内外周血CD3~+、CD4~+和CD8~+T细胞频率显著高于CHB组和对照组,NK细胞4周内均低于其余2组(P<0.05).AHB疾病早期ALT高水平异常时CD4~+/CD8~+明显低下;随着ALT恢复正常,CD4~+/CD8~+比值呈逐渐升高趋势.结论 AHB患者外周血免疫细胞的分布与对照组和CHB患者不同,淋巴细胞亚群的动态变化与疾病发展可能有一定的相关性.     

癫痫患者血浆神经肽Y与免疫细胞的水平变化及其临床意义

目的观察颞叶癫痫患者不同时期外周血T淋巴细胞亚群、NK细胞和神经肽Y(NPY)的水平,探讨癫痫与神经免疫学之间的关系。方法将符合诊断标准36例颞叶癫痫患者入院10 min内和入院24 h的外周血中免疫细胞及NPY的水平与入院时进行比较分析。结果入院10 min内外周血中白细胞总数、中性粒细胞、淋巴细胞、NK细胞及NPY的水平均较入院时明显升高(P<0.05),而CD4细胞则降低13%;NPY与NK细胞水平之间呈正相关(r=0.839,P<0.05);入院24 h外周血中免疫细胞与入院时水平无显著性差异(P>0.05)。结论癫痫患者存在免疫功能低下,癫痫发作后血浆NPY含量明显增加,NPY可能参与免疫功能的调节。     

弱智儿童的ABS测定

世界卫生组织规定,社会适应能力是诊断弱智的三个必备条件之一,应用AAMD—ABS量表对63名弱智儿童进行了量表测定,并与正常儿童对照,结果表明:弱智儿童的社会适应能力(第一部分)与正常儿童有明显差异,与智商有明显相关。     

Sister-chromatid exchanges in the lymphocytes of people exposed to environmental cadmium

Sister-chromatid exchanges (SCEs) were analyzed from peripheral lymphocyte cultures of 8 men and 16 women who had been exposed to environmental cadmium (Cd), and 6 controls. Average Cd concentrations in blood of the Cd-polluted group were 8.9 micrograms/l for men and 10.0 micrograms/l for women. These were no significant differences in SCE rates between the Cd-polluted and nonpolluted groups. There were no significant correlations between SCE rates and blood or urinary Cd concentrations. Cadmium alone may be an insignificant agent in producing chromosomal damage to peripheral blood lymphocytes.     

Reduced Phenotypic Severity Following Adeno-Associated Virus-Mediated Fmr1 Gene Delivery in Fragile X Mice

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide repeat expansion in the FMR1 gene that codes for fragile X mental retardation protein (FMRP). To determine if FMRP expression in the central nervous system could reverse phenotypic deficits in the Fmr1 knockout (KO) mouse model of FXS, we used a single-stranded adeno-associated viral (AAV) vector with viral capsids from serotype 9 that contained a major isoform of FMRP. FMRP transgene expression was driven by the neuron-selective synapsin-1 promoter. The vector was delivered to the brain via a single bilateral intracerebroventricular injection into neonatal Fmr1 KO mice and transgene expression and behavioral assessments were conducted 22–26 or 50–56 days post injection. Western blotting and immunocytochemical analyses of AAV–FMRP-injected mice revealed FMRP expression in the striatum, hippocampus, retrosplenial cortex, and cingulate cortex. Cellular expression was selective for neurons and reached ∼50% of wild-type levels in the hippocampus and cortex at 56 days post injection. The pathologically elevated repetitive behavior and the deficit in social dominance behavior seen in phosphate-buffered saline-injected Fmr1 KO mice were reversed in AAV–FMRP-injected mice. These results provide the first proof of principle that gene therapy can correct specific behavioral abnormalities in the mouse model of FXS.     

Reducing histone acetylation rescues cognitive deficits in mouse model of fragile X syndrome

Fragile X syndrome(FXS) is the most prevalent inherited intellectual disability, resulting from a loss of fragile X mental retardation protein(FMRP). Patients with FXS suffer lifelong cognitive disabilities, but the function of FMRP in the adult brain and the mechanism underlying age-related cognitive decline in FXS is not fully understood. Here, we report that a loss of FMRP results in increased protein synthesis of histone acetyltransferase EP300 and ubiquitinationmediated degradation of histone deacetylase HDAC1 in adult hippocampal neural stem cells(NSCs). Consequently, FMRPdeficient NSCs exhibit elevated histone acetylation and age-related NSC depletion, leading to cognitive impairment in mature adult mice. Reducing histone acetylation rescues both neurogenesis and cognitive deficits in mature adult FMRPdeficient mice. Our work reveals a role for FMRP and histone acetylation in cognition and presents a potential novel therapeutic strategy for treating adult FXS patients.     

Effects of iron therapy on cognition in anemic school going boys

The present study was conducted on 18 anemic and 34 control subjects (mean age 9.26 +/- 0.26 years) to observe the effect of anemia on cognition and to see effect of 3 months of iron therapy on it. Anemia was defined on the basis of hematological values and peripheral smear examinations. Cognitive data consisted of the recording of the P300 wave of Auditory Event Related Potentials (AERP), Ravens Progressive Matrices Test (RPMT), and Digit Span Attention Test (DSAT) under standard test conditions. RPMT scores were then converted to the intelligence quotient (IQ) scores for comparison. Both anemic and control boys were dewormed after recording pretreatment values and then anemic boys were given iron therapy for 3 months, after which the recordings were taken again. Pretreatment, anemic boys showed significantly lower hematological values, delayed P300 latency, and lower RPMT scores as compared to controls. Post therapy the hematological profile of anemic boys though significantly improved as compared to the pretreatment values, was still significantly lower than that of control boys. The P300 latency values of anemic boys showed improvement but were still significantly delayed than the control group. RPMT values and derived IQ scores of anemic boys were similar to control boys after therapy suggesting that though the 3 months iron therapy regime resulted in improvement in psychometric cognitive tests in anemic boys, the basic P300 defects persisted. This suggests that the P300 component of AERP in anemic children is relatively refractory to 3 months of iron therapy.     

早期手术治疗对鼾症患儿智力发育的影响

目的 探讨早期手术治疗对鼾症患儿智力发育的影响,为小儿鼾症早期手术提供重要依据.方法 对鼾症患儿40例行双侧扁桃体和/或腺样体切除术（观察组）,采用中国-韦氏幼儿智力量表（C-WYCSI）进行术前和术后6个月的智力测试,包括语言智商和操作智商两部分共11项分测试;操作智商又包括视觉分析测验（VA）和几何图形测验（GD）两类.按照1∶1匹配选择同性别、同年龄（±3个月）、家庭条件相当的健康体检学龄前期儿童40例作为对照组进行比较.结果 观察组术前总智商、言语智商、操作智商分别为82、81、83,均低于对照组的101、101、101（t=4.131、3.952、3.842,均P＜0.05）;术后总智商、言语智商及操作智商分别为98、98、99,均在正常范围,与对照组差异均无统计学意义（均P＞0.05）.结论 鼾症患儿早期手术治疗可以改善患儿智力;鼾症患儿影响呼吸并有手术指征者,宜早期手术治疗.     

放射治疗对鼻咽癌病人智力和记忆力的影响

目的探讨放射治疗对鼻咽癌患者智力和记忆力的影响。方法选择30例放疗后的鼻咽癌患者和30例年龄及文化相匹配的待放疗的鼻咽癌患者,分别进行韦氏智力量表(WAIS- RC)和韦氏记忆量表(WMS-RC)测验。结果两组病例的总智商(FIQ)和分智商中的言语智商(VIQ)及操作智商(PIQ)均无显著性差异(P>0．0 5);两组病例的记忆商数(MQ)无显著性差异(P>0．05),但在再生一个分测验项目上,差异接近统计学意义(P=0．05)。结论放射治疗对鼻咽癌患者的智力和记忆力无明显影响。     

抽动障碍患者智力及智力结构测定

目的了解抽动障碍患者智力状况及其结构特点,探讨各亚型之间智力状况是否存在差别,氟哌啶醇、泰必利等药物对智力是否有影响。方法应用中国-韦氏儿童智力量表(C-WISC)测定38例抽动障碍患者(病例组)总智商(FIQ)、言语智商(VIQ)、操作智商(PIQ),并与20例正常儿童(对照组)进行比较。结果病例组FIQ为(98.71±13.07),VIQ为(104.63±14.42),PIQ为(92.13±12.02),对照组FIQ为(108.25±14.35),VIQ为(114.00±15.54),PIQ为(99.55±11.97)。两组间各均值比较,差异有显著意义(P<0.05)。病例组各亚型之间FIQ、VIQ、PIQ比较,差异均无显著意义(P>0.05)。病例组中治疗组与未治疗组之间FIQ、VIQ、PIQ比较,差异均无显著意义(P>0.05)。结论抽动障碍患者存在一定程度的智力缺陷,在治疗该类患者的过程中值得参考。抽动障碍各亚型之间智力无明显差别。氟哌啶醇、泰必利等药物治疗抽动障碍对智力无影响。     

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.     

The role of fragile X mental retardation protein in major mental disorders

Fragile X mental retardation protein (FMRP) is highly enriched in neurons and binds to approximately 4% of mRNAs in mammalian brain. Its loss is a hallmark of fragile X syndrome (FXS), the most common form of mental retardation. In this review we discuss the mutation in the fragile X mental retardation-1 gene (FMR1), that leads to FXS, the role FMRP plays in neuronal cells, experiments from our own laboratory that demonstrate reductions of FMRP in additional psychiatric disorders (autism, schizophrenia, bipolar disorder, and major depressive disorder), and potential therapies to ameliorate the loss of FMRP. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.