动态突变的产生、致病作用及主要相关疾病

基因内或侧翼序列的一些 DNA重复序列与许多人类遗传病的发病有关。这些 DNA重复序列主要包括 CAG、CCG、CTG等三核苷酸重复序列 ,以及其他长度不等的小卫星、微卫星重复序列等。它们的拷贝数在世代传递的过程中发生扩增 ,并常在体细胞中发生长短不等的扩增而造成体细胞的嵌合性。这种不稳定的突变形式称为动态突变。发生动态突变的DNA重复序列通过导致基因功能丢失或获得异常表达产物等途径致病。目前已知的动态突变疾病大约有 2 0种。本文就动态突变有关的新进展作一论述。     

动态突变的产生、致病作用及主要相关疾病

基因内或侧翼序列的一些DNA重复序列与许多人类遗传病的发病有关。这些DNA重复序列主要包括CAG、CCG、CTG等三核苷酸重复序列．以及其他长度不等的小卫星、微卫星重复序列等。它们的拷贝数在世代传递的过程中发生扩增．并常在体细胞中发生长短不等的扩增而造成体细胞的嵌合性。这种不稳定的突变形式称为动态突变。发生动态突变的DNA重复序列通过导致基因功能丢失或获得异常表达产物等途径致病。目前已知的动态突变疾病大约有20种。本文就动态突变有关的新进展作一论述。     

非编码区三核苷酸重复序列动态突变及相关疾病机制的研究进展

三核苷酸重复序列普遍存在于真核生物基因组。三核苷酸重复序列的动态突变与多种人类遗传疾病密切相关。这种动态突变可发生在基因的编码区和非编码区。非编码区三核苷酸动态突变引起的疾病有脆性X综合症 (FragileXsyndrome)、强直性肌营养不良症 (DM )、Friedreich共济失调 (FRDA) ,其遣传不稳定机制为发夹模式和重组修复 (基因转变 )模式     

三核苷酸重复序列（GAA·TTC）n扩增的分子机制研究现状

三核苷酸重复DNA序列普遍存在于人类基因组中。迄今已经发现有4种三核苷酸重复序列的扩增或不稳定,可以导致40多种人类神经退行性疾病。其中,Friedreich’sataxia综合征是由位于FXN基因第1个内含子中（GAA·TTC）。序列扩增引起。最近有关（GAA·TTC）。扩增的研究进展表明：（GAA·TTC）。重复序列可以形成非-B型二级结构,并有可能由此造成重复序列的扩增或干扰重复序列的稳定性。同时,重复序列经RNA转录为hnRNA之后的加工以及疾病染色体位点处的表遗传学控制也可能与（GAA·TTC）。的稳定性维护有关。     

SCA1转基因小鼠:一个CAG三核苷重复扩增引起的神经变性的研究模型

1型脊髓小脑运动失调(spinocelebellar ataxia typ 1,SCA1)是常染色体显性遗传病,其特征为由于不稳定的CAG三核苷酸重复扩增引起的小脑浦肯野细胞、脊髓小脑后束和选择性的脑干神经元退行性变。为了弄清SCA1突变的发病机理以及三核苷酸重复在小鼠代际间的遗传稳定性,作者用表达带有正常或CAG反复扩增序列的人类SCA1基因的转基因小鼠进行研究。两种基因在从亲代向子代的遗传过程中都是稳定的。表达无CAG扩增序列的     

三核苷酸重复序列(GAA·TTC)_n扩增的分子机制研究现状

三核苷酸重复DNA序列普遍存在于人类基风组中.迄今已经发现有4种三核苷酸重复序列的扩增或不稳定,可以导致40多种人类神经退行性疾病.其中,Friedreich's ataxia综合征是由位于FXN基因第1个内含子中(GAA·TTC)_n序列扩增引起.最近有关(GAA·TTC)_n扩增的研究进展表明:(GAA·TTC)_n重复序列可以形成非-B型二级结构,并有可能由此造成重复序列的扩增或干扰重复序列的稳定性.同时,重复序列经RNA转录为hnRNA之后的加工以及疾病染色体位点处的表遗传学控制也可能与(GAA·TTC)_n的稳定性维护有关.     

遗传性神经疾病的分子生物学

九十年代以来,神经分子生物学研究日益成为神经生物学研究中的一个新生长点,越来越多的与神经疾病有关的基因被克隆分离,涉及神经肌肉疾病,神经退行性变性和与三核苷酸重复序列突变有关的疾病,本文选择其中较有代表性的几种遗传性神经疾病的分子生物学研究结果予以综述。     

不稳定三核苷酸重复序列与遗传性神经精神疾患

不稳定三核苷酸重复序列与遗传性神经精神疾患严韶峰，黄尚志（中国协和医科大学北京１００００５）自１９９１年克隆分离获得脆Ｘ综合征（Ｆｒａｇｉｌｅ－Ｘｓｙｎｄｒｏｍｅ，ＦｒａＸ）相关基因并确定其致病突变为基因内（ＣＧＧ）ｎ重复序列高度膨胀以来［１］，动态...     

一种可遗传的不稳定DNA序列

一种可遗传的不稳定ＤＮＡ序列沈福民，胡应近两年，在人类遗传学中发现一种新的基因突变机理或新的遗传机理。即三核苷酸重复片段扩增突变，（ｔｒｉｎｕｃｌｅｏｔｉｄｅｒｅｐｅａｔｅｘｐａｎｓｉｏｎｍｕｔａｔｉｏｎｓ，ＴＲＥＭ）［１］。人们又将这段三核苷酸重复...     

非编码区核苷酸重复扩增导致的三种脊髓小脑型共济失调亚型分子基础

遗传性脊髓小脑型共济失调(hereditary spinocerebellar ataxias,SCAs)的发病大部分与基因编码区三核苷酸CAG/CAA的异常重复有关,而SCA8、SCA10、SCA12的发病分别与致病基因非编码区CTA/CTG、ATILT和CAG的异常重复突变有关;近来的研究主要集中在3种亚型的遗传特征和发病机制上面,如核苷酸重复的不稳定性不同外显率的改变、疾病遗传的性别偏倚和遗传早现现象等.由于非编码区核苷酸重复对翻译成多聚谷氨酰胺蛋白的影响不大,3种SCA亚型的发病机制和其它SCAS严型完全不同,核苷酸的异常重复对DNA转录的干扰、转录后含异常核苷酸重复的RNA的毒性作用以及重复序列不同方向上的双向转录机制在3种SCA业型的发病机制中可能起到了关键作用.     

No association of the SCA1 (CAG)31 allele with Huntington's disease, myotonic dystrophy type 1 and spinocerebellar ataxia type 3

Trinucleotide repeat expansions are the underlying mutation in several neurodegenerative and neuromuscular disorders including at least eight spinocerebellar ataxias (SCA). The molecular mechanisms of repeat expansion are as yet insufficiently understood. Recently, an association of the SCA1 (CAG)31 repeat allele with Huntington's disease and myotonic dystrophy type 1 was described. These findings implicate a possible role of the SCA1 (CAG)31 allele in other triplet diseases. We analyzed the SCA1 CAG repeat length in a large sample of Huntington's disease (n=182), myotonic dystrophy type 1 (n=64) and SCA3 (n=31) patients. In none of these groups was a significant association with the 31 repeat allele found. Our findings do not support the hypothesis that this allele is involved in the etiology of trinucleotide expansion.     

Medical pathology due to trinucleotide repeats

Trinucleotide repeat expansion is responsible for ten human diseases described so far. Four types of repeats are involved in these expansions, with type, number and position in the gene varying from one disease to another. In some fragile sites, the trinucleotide repeat is found to be enlarged to 200 or more. Smaller expansions have been found within coding regions of some genes that are associated with neurodegenerative diseases, such as Huntington's disease. The continuous expansion of the trinucleotide repeats in subsequent generations explains the genetic anticipation, peculiar to these disorders. Recently, it was shown that two expanded minisatellite sequences are also involved in both progressive myoclonus epilepsy type 1 and distamycin A-sensitive fragile site, FRA16B. This form of peculiar heredity is very important because of its relationship with some of the common human degenerative diseases.     

Sequencing analysis of the spinal bulbar muscular atrophy CAG expansion reveals absence of repeat interruptions

Trinucleotide repeat disorders are a heterogeneous group of diseases caused by the expansion, beyond a pathogenic threshold, of unstable DNA tracts in different genes. Sequence interruptions in the repeats have been described in the majority of these disorders and may influence disease phenotype and heritability. Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by a CAG trinucleotide expansion in the androgen receptor (AR) gene. Diagnostic testing and previous research have relied on fragment analysis polymerase chain reaction to determine the AR CAG repeat size, and have therefore not been able to assess the presence of interruptions. We here report a sequencing study of the AR CAG repeat in a cohort of SBMA patients and control subjects in the United Kingdom. We found no repeat interruptions to be present, and we describe differences between sequencing and traditional sizing methods.     

Intergenerational CAG repeat expansion at ERDA1 in a family with childhood-onset depression, schizoaffective disorder, and recurrent major depression

Reported evidence of anticipation for schizophrenia and bipolar disorder has recently precipitated a search for unstable trinucleotide repeats for these diseases. Several initial studies suggested an increase in the frequency of large CAG/CTG repeats in the genomes of schizophrenic and bipolar individuals. Published reports do not demonstrate expansion per se, and may be suggestive of allelic association with the disease rather than actual dynamic DNA mutations. This report documents evidence of a significant expansion of CAG/CTG repeats from one generation to the next in a family demonstrating evidence of anticipation for psychiatric disorders. Using the repeat expansion detection (RED) technique, we observed that a proband with multiple psychiatric diagnoses, including childhood-onset depression, inherited a larger CAG/CTG repeat than either parent. Analysis of the ERDA1 locus on 17q21.3 revealed that the proband inherited a very large allele from the father which increased in repeat number through transmission. The mother was diagnosed with schizoaffective disorder and the father with depression. While this DNA mutation may be a stochastic event unconnected with the disease, it could represent DNA instability as an etiologic factor in psychiatric diseases.     

Inherited Neurodegenerative Disorders Caused by CAG/Polyglutamine Tract Expansions: Symposium Introduction

At the beginning of this decade, the American Association of Neurology decided that the 1990's should be labelled "the decade of the brain" for expected advances in our understanding of neurological disorders and neuroscience. By the end of this decade, clinicians and researchers who work in the field of inherited neurological disorders might well remember the 1990's as "the decade of the trinucleotide repeat". At the time of writing this introduction, eleven inherited neurological disorders have been found to be caused by expansions of trinucleotide repeats, and a twelfth trinucleotide repeat expansion mutation has been identified (6), although the gene containing this mutant triplet repeat has not been cloned to our knowledge (Table 1).     

The extinction program for Homo sapiens and cloning humans: trinucleotide expansion as a one-way track to extinction

It has been uncovered that expansion of trinucleotide repeats in the human genome are causing a variety of genetic diseases. They are also identified in other loci that are not clearly related to particular diseases, which indicates such repeat expansion is one of the general forms of evolution occurring throughout the human genome. Trinucleotide repeat expansion has been shown to occur during meiosis, and is generally irreversible. In consequence, every human chromosome suffers from the burden of accumulating trinucleotide repeats along with the passage of generation, which eventually ends up in a deficiency of replication. Thus, all the human chromosomes are predicted to be 'mortal', so far as they replicate through meiosis. Naturally, the mortality of human chromosomes leads to the mortality of Homo sapiens as a species on earth. Although it is quite controversial, a radical breakthrough for humans to survive might be found through cloning reproduction without meiosis.     

Trinucleotide Repeat Instability: Genetic Features and Molecular Mechanisms

Trinucleotide repeat expansions are an important cause of inherited neurodegenerative disease. The expanded repeats are unstable, changing in size when transmitted from parents to offspring (inter-generational instability, "meiotic instability") and often showing size variation within the tissues of an affected individual (somatic mosaicism, "mitotic instability"). Repeat instability is a clinically important phenomenon, as increasing repeat lengths correlate with an earlier age of onset and a more severe disease phenotype. The tendency of expanded trinucleotide repeats to increase in length during their transmission from parent to offspring in these diseases provides a molecular explanation for anticipation (increasing disease severity in successive affected generations). In this review, I explore the genetic and molecular basis of trinucleotide repeat instability. Studies of patients and families with trinucleotide repeat disorders have revealed a number of factors that determine the rate and magnitude of trinucleotide repeat change. Analysis of trinucleotide repeat instability in bacteria, yeast, and mice has yielded additional insights. Despite these advances, the pathways and mechanisms underlying trinucleotide repeat instability in humans remain largely unknown. There are many reasons to suspect that this uniquely human phenomenon will significantly impact upon our understanding of development, differentiation and neurobiology.     

Fragile X syndrome: the FMR1 CGG repeat distribution among world populations

Fragile X syndrome (FXS) is characterized by moderate to severe intellectual disability, which is accompanied by macroorchidism and distinct facial morphology. FXS is caused by the expansion of the CGG trinucleotide repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. The syndrome has been studied in ethnically diverse populations around the world and has been extensively characterized in several populations. Similar to other trinucleotide expansion disorders, the gene-specific instability of FMR1 is not accompanied by genomic instability. Currently we do not have a comprehensive understanding of the molecular underpinnings of gene-specific instability associated with tandem repeats. Molecular evidence from in vitro experiments and animal models supports several pathways for gene-specific trinucleotide repeat expansion. However, whether the mechanisms reported from other systems contribute to trinucleotide repeat expansion in humans is not clear. To understand how repeat instability in humans could occur, the CGG repeat expansion is explored through molecular analysis and population studies which characterized CGG repeat alleles of FMR1. Finally, the review discusses the relevance of these studies in understanding the mechanism of trinucleotide repeat expansion in FXS.