结节性硬化症分子生物学研究进展

结节性硬化症的分子病理机制尚未完全阐明,其致病基因TSC1和TSC2编码的错构瘤蛋白和结节蛋白具有肿瘤抑制作用,是细胞生长和增殖的重要调节因子。以往对结节性硬化症的研究多关注TSC1和TSC2基因缺失和突变,本文旨在对结节性硬化症的分子生物学研究进展做一综述。     

结节性硬化症分子生物学研究进展

结节性硬化症的分子病理机制尚未完全阐明，其致病基因TSC1和TSC2编码的错构瘤蛋白和结节蛋白具有肿瘤抑制作用，是细胞生长和增殖的重要调节因子。以往对结节性硬化症的研究多关注TSC1和TSC2基因缺失和突变，本文旨在对结节性硬化症的分子生物学研究进展做一综述。     

结节性硬化症TSC1/TSC2基因突变的高通量测序快速诊断

目的建立结节性硬化症TSC1/TSC2基因高通量测序技术以快速准确检测结节性硬化的TSC基因突变。方法对10例结节性硬化症患者及10例正常对照进行研究,利用长链PCR方法扩增TSC1及TSC2基因所有外显子区域,运用Ion PGMTM平台进行二代测序并运用常规测序验证。结果设计引物对TSC1及TSC2基因特异性扩增出7个长片段产物,产物长度介于13 kb~15 kb间;运用二代测序技术快速鉴定出10个致病突变,其中,7个突变位于TSC2基因,3个突变位于TSC1基因;所有突变经常规Sanger测序验证,结果一致。结论高通量二代测序技术可快速可靠诊断结节性硬化症TSC1、TSC2基因突变。     

结节性硬化症分子遗传学研究进展

近 10年 ,结节性硬化症 (TSC)的分子遗传学研究取得很大进展 ,致病基因为 TSC1和 TSC2 ,其产物分别为错构瘤蛋白和马铃薯球蛋白 ,本文综述了 TSC1和 TSC2的定位、结构、基因产物、功能、突变型 /表现型之间的关系     

一例结节性硬化症家系的 TSC基因变异分析及产前诊断

目的:分析1个结节性硬化症(tuberous sclerosis complex,TSC)家系 TSC1和 TSC2基因变异位点并进行产前诊断。 方法:应用Sanger测序法分别对先证者及其家庭成员进行 TSC1和 TSC2基因变异检测分析。 结果:家...     

结节性硬化症分子遗传学研究进展

近10年，结节性硬化症（TSC）的分子遗传学研究取得很大进展，致病基因为TSC1和TSC2，其产物分别为错构瘤蛋白和马铃薯球蛋白，本综述了TSC1和TSC2的定位，结构，基因产物，功能，突变型/表现型之间的关系。     

一个结节性硬化症家系致病基因新突变鉴定

目的结节性硬化症(TSC)是一种累及多系统的常染色体显性遗传病,以全身多种组织器官出现错构瘤样增生为主要特征,其致病基因为TSC1和TSC2基因,本研究旨在对一中国汉族结节性硬化症家系进行基因突变分析,以明确临床诊断并指导遗传咨询。方法设计PCR引物,扩增TSC1和TSC2外显子及外显子-内含子交界区并进行Sanger测序和片段克隆测序分析,确定突变位点并探讨突变致病的可能机制。结果 TSC1基因测序分析发现先证者第15外显子存在两个杂合突变,c.1556CT和c.1888_1891del AAAG。克隆测序结果显示,先证者的两个突变均来自于同一个等位基因。第一个突变可能影响TSC1与粘着斑激酶家族作用蛋白FIP200的结合,第二个突变形成了提前的终止密码,推测可能形成截短的蛋白分子,或者通过无义介导的m RNA降解机制被降解而致病。结论TSC1基因c.1556CT和c.1888_1891del AAAG为结节性硬化症家系致病突变,对患者明确诊断及遗传咨询有重要意义。     

一例 TSC2基因嵌合变异致结节性硬化症患者的遗传学分析

目的:对1个结节性硬化症(tuberous sclerosis complex, TSC)家系进行 TSC1和 TSC2基因变异分析,明确其可能的致病原因。 方法:采集患者及其父母的外周血样,提取基因组DNA,应用靶向二代测序联合Sanger测序进行患者及其父母 TSC1和...     

TSC基因的生物学作用

TSC基因TSC1和TSC2分别编码蛋白hamartin和tuberin,最初在结节性硬化症中发现其存在突变,作为肿瘤抑制因子,除参与mTOR信号途径调节细胞的生长和增殖外,还参与细胞黏附,细胞内吞等过程的调节.     

肺多发结节囊性病变罕见原因结节性硬化症1例

目的 扩展临床对肺多发囊性病变和多结节病变的鉴别诊断思维,深化对结节性硬化症(TSC)这一罕见疾病表现多样性的认识。方法 报告了1例以体检发现肺部弥漫病变就诊的结节性硬化症患者的临床诊治过程,并结合相关文献进行探讨。结果 进一步检查发现患者有心脏多发混杂密度影、肝内散在小结节、双肾多发结节占位、全身多发成骨病灶等多系统累及,肾结节行经皮穿刺活检病理示血管平滑肌脂肪瘤;结合患者皮肤散在小点片状色素脱失斑提示了TSC可能性;进一步外周血全外显子测序诊断为TSC。西罗莫司治疗后肺内病变好转。结论 成人多发囊性肺疾病和多结节肺病鉴别诊断应考虑TSC的可能性。深入认识TSC各系统表现对早诊断早治疗TSC至关重要。     

Schizophrenia in a North Swedish geographical isolate, 1900–1977. Epidemiology, genetics and biochemistry

Over 200 schizophrenic patients belonging to three major and interrelated pedigree complexes have been investigated over the past 30 years in a North Swedish geographically isolated population, presently numbering about 6,000. An intensive investigation of a number of biochemical correlates and genetic markers in a few selected families belonging to one of the major pedigrees has indicated new strategies for the current research program.
Schizophrenia, as defined operationally, is significantly associated with decreased activities of two enzymes (1) blood platelet monoamine oxidase, (2) plasma dopamine-β-hydroxylase, and (3) with the genetic marker Gc² (group specific antigen). Both enzymes are subject to genetic variation. A positive score for linkage between schizophrenia and low plasma DBH activity has been calculated, but, so far, available data are insufficient for discrimination between linkage and partial contribution of genetically controlled low plasma DBH to the pathogenesis of the disease. Alternatively, both mechanisms could be involved.
As a model for continued research, schizophrenia is explained as based on a double dominant-recessive genotype (Aabb), representing a vulnerability which in about 50 % of cases develops into clinical schizophrenia. It is suggested that the dominant mutation (A) operates on or affects MAO activity, and that the recessive genotype (bb) is instrumental in low variates of DBH activity and very likely such variates within the normal range of physiological variation. Moreover, it is suggested that the combined effects of MAO- and DBH-reduced efficiency on the metabolism of e.g. dopamine could be an essential pathogenic mechanism for the schizophrenic illness which is segregating in this population.     

Renal dysplasia and asplenia in two sibs

A family is reported in which two sibs, one male and the other female, both died within 24 hours of birth with enlarged polycystic kidneys. Postmortem histology in the second child showed gross renal dysplasia. In both children the pancreas was enlarged, nodular and cystic but the liver appeared macroscopically normal. In the second child, histological examination confirmed pancreatic fibrosis with cystic dilation of ducts, but showed portal fibrosis with bile duct proliferation in the liver.
This combination of findings is very reminiscent of those in a girl and her brother reported by Ivemark et al. (1959). The children reported here also showed absence or hypoplasia of the spleen, cardiac anomalies and other features of the Ivemark syndrome (Ivemark 1955), a quite different, usually sporadic, congenital disorder. It is suggested that the children described here have a distinct lethal congenital disorder, probably inherited in an autosomal recessive manner.     

Role of cholinergic and serotoninergic processes in modulation of activity of the negative reinforcement system

The effect of cholinergic and serotoninergic drugs on the latency of blocking of central aversive stimulation was studied. Physostigmine and fluoxetin increased the latency of avoidance. Hyoscine and n-chloramphetamine could either increase or decrease the time of active avoidance. Fluoxetin reduced the activating and reversed the depriming effects of hyoscine. A combination of fluoxetin with physostigmine potentiated the depressant effect of the latter. n-Chloramphetamine weakened inhibitory effect of physostigmine and potentiated the action of hyoscine. An inhibitory role is suggested for cholinergic and serotoninergic mechanisms in the activity of the negative reinforcement system. Functional interconnection between these neuromediator systems is postulated.Department of Pharmacology, Academician I. P. Pavlov First Medical Institute, Leningrad. (Presented by Academician of the Academy of Medical Sciences of the USSR S. V. Anichkov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 86, No. 11, pp. 552–554, November, 1978.     

The universal muscular chamber. A basic unit of the genitourinary, cardiovascular, gastro-intestinal, skeletal, cutaneous, respiratory and other systems, endocameral hypertension; and spasm, the key to their idiopathic diseases and arthropathies

Starting with the integument, we see many organs are contractile sacs or multiples thereof, which tubes or bags constitute the major part of the entire body. Recognition of this basic unit and its characteristics sheds new light, individually and collectively, on many disorders previously considered unrelated. Muscular tears and perforations develop in the walls of these chambers, being no way peculiar to those organs, wherein, hydrochloric acid occurs. So, it is not necessary to explain the absence of excessive acid from patients who exhibit holes in the gastric, uterine, aortic, duodenal, rectal, pulmonary, retina, and other walls. Muscle, not acid is the great common factor relating idiopathic disorders in the gastrointestinal tract to each other and to similar diseases in other systems. When the units are linked together, the lesions tend to appear as arthropathies, i.e. at the joints. Rephrasing common-place observations, frees us from conventional, conceptual cul-de-sacs. An observation is only as good as its interpretation, so all possibilities must be considered, otherwise, we will remain blinded by our misconceptions.     

Chemotherapy and antiangiogenesis: drug-specific effects on microvessel sprouting

Tumors are angiogenesis dependent. Some chemotherapeutics have been shown to be able to suppress angiogenesis and thus tumor growth in vivo at low, well-tolerated doses. Not much is known about the angiogenesis-modulating effects of chemotherapeutics in vivo, however. Microvessel sprouting is inherent to angiogenesis. Using the rat mesentery assay, we studied the effect of cyclophosphamide, doxorubicin and paclitaxel at a low, atoxic dose on the number of sprouts per unit tissue volume (No. SP) and their length (Le. SP) at the edge of the expanding network in VEGF165-mediated angiogenesis. A single dose of each cytotoxic drug was administered i.v. 7 days before the animals were sacrificed. Cyclophosphamide significantly lengthened the shortest Le. SP and shortened the longest Le. SP, doxorubicin did not significantly affect Le. SP, whereas paclitaxel significantly shortened both the shortest and the longest Le. SP. No correlation was found between the present results and the distinctly drug-specific results of microvessel segment number and length analyzed within central parts of the same expanding network. To our knowledge, this is the first quantitative report on the effect of chemotherapy on angiogenesis sprouting in vivo. Collectively, the data suggest that cyclophosphamide, doxorubicin and paclitaxel at a non-toxic dose primarily target different intrinsic components of the angiogenic cascade, leading to distinctly drug-specific effects.     

Experimental study of the possibility of metabolic correction of maternal, fetal, and newborn hypoxia in rats using a new amino acid composition MR-33

The status of pregnant rats, their fetuses, and progeny exposed to oxygen insufficiency are compares. By the end of pregnancy the resistance to hypoxia markedly decreases. Newborn rats during nursing are highly resistant to hypoxia. When nursing period is over, the resistance to hypoxia drops, but later is gradually restored. MR-33 preparation produces a pronounced antihypoxic effect. Administration of the drug to pregnant rats not only appreciably improves their resistance to oxygen insufficiency, but also promotes adaptation and compensatory mechanisms in the progeny, thus helping the progeny to better tolerate hypoxia, particularly when its probability is particularly high. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 124, No. 10, pp. 451–454, October, 1997     

Changes in state of the surfactant in experimental pneumonia

The state of the lung surfactant in rabbits at different stages of development of experimental pneumonia (3–60 days) was compared with the dynamics of oxidoreductases in the alveolar epithelium and cells of the inflammatory focus of infiltration. In the initial stage (3–7 days) of activation of cell metabolism there was a brief increase in, the intensity of surfactant lipid synthesis, accompanied by relative inhibition of phospholipid synthesis. Later, development of degenerative changes and sclerosis of the parenchyma was accompanied by inhibition of synthesis of all components of the surfactant. The surface activity of the surfactant became stabilized at a low level.Laboratory Division, I. M. Sechenov Research Institute of Medical Climatology and Physical Methods of Treatment, Yalta. Department of Pathological Anatomy, Faculty of Internal Medicine, and Department of Organic Chemistry, Crimean Medical Institute, Simferopol'. (Presented by Academician of the Academy of Medical Sciences of the USSR A. M. Chernukh.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 9, pp. 286–288, September 1977.     

Response of different types of connective tissue to hormones

A comparative study was made of the lysosomal glycosidases of the eye tissues (sclera and cornea) and also of bone tissue and cartilage from rabbits. Intraperitoneal injection of thyrocalcitonin (TCT), deoxycorticosterone (DOC), hydrocortisone (HC), and somatotropic hormone (STH) were shown to modify the activity of -galactosidase, -glucosidase, and hyaluronidase and the functional state of the lysosomal membranes in the tissues. HC and STH stabilize, whereas DOC and large doses of TCT labilize the lysosomal membranes. After injection of HC and STH the absolute activity of the enzymes in the tissue homogenates falls, whereas DOC has the opposite action.Helmholtz Research Institute for Eye Diseases, Moscow. N. N Priorov Central Scientific-Research Institute of Traumatology and Orthopedics, Moscow. (Presented by Academicial of the Academy of Medical Sciences of the USSR M. V. Volkov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 7, pp. 38–41, July, 1977.     

Hypermethioninemias of genetic and non-genetic origin: A review

This review covers briefly the major conditions, genetic and non-genetic, sometimes leading to abnormally elevated methionine, with emphasis on recent developments. A major aim is to assist in the differential diagnosis of hypermethioninemia. The genetic conditions are: (1) Homocystinuria due to cystathionine β-synthase (CBS) deficiency. At least 150 different mutations in the CBS gene have been identified since this deficiency was established in 1964. Hypermethioninemia is due chiefly to remethylation of the accumulated homocysteine. (2) Deficient activity of methionine adenosyltransferases I and III (MAT I/III), the isoenzymes the catalytic subunit of which are encoded by MAT1A. Methionine accumulates because its conversion to S-adenosylmethionine (AdoMet) is impaired. (3) Glycine N-methyltrasferase (GNMT) deficiency. Disruption of a quantitatively major pathway for AdoMet disposal leads to AdoMet accumulation with secondary down-regulation of methionine flux into AdoMet. (4) S-adenosylhomocysteine (AdoHcy) hydrolase (AHCY) deficiency. Not being catabolized normally, AdoHcy accumulates and inhibits many AdoMet-dependent methyltransferases, producing accumulation of AdoMet and, thereby, hypermethioninemia. (5) Citrin deficiency, found chiefly in Asian countries. Lack of this mitochondrial aspartate-glutamate transporter may produce (usually transient) hypermethioninemia, the immediate cause of which remains uncertain. (6) Fumarylacetoacetate hydrolase (FAH) deficiency (tyrosinemia type I) may lead to hypermethioninemia secondary either to liver damage and/or to accumulation of fumarylacetoacetate, an inhibitor of the high K(m) MAT. Additional possible genetic causes of hypermethioninemia accompanied by elevations of plasma AdoMet include mitochondrial disorders (the specificity and frequency of which remain to be elucidated). Non-genetic conditions include: (a) Liver disease, which may cause hypermethioninemia, mild, or severe. (b) Low-birth-weight and/or prematurity which may cause transient hypermethioninemia. (c) Ingestion of relatively large amounts of methionine which, even in full-term, normal-birth-weight babies may cause hypermethioninemia.