全基因组关联研究现状

在过去的5年中, 全基因组关联研究(Genome-wide association study, GWAS)方法已被证明是研究复杂疾病和性状遗传易感变异的一种有效手段。目前, 各国科学家在多种复杂疾病和性状中开展了大量的GWAS, 对肿瘤、糖尿病、心脏病、神经精神疾病、自身免疫及免疫相关疾病等复杂疾病以及一些常见性状(如身高、体重、血脂、色素等)的遗传易感基因研究取得了重大成果。截止到2010年9月11日, 运用GWAS开展了对近200种复杂疾病/性状的研究, 发现了3 000多个疾病相关的遗传变异。文章就GWAS的发展及其在复杂疾病/性状中的应用做一综述。     

Mitochondrial DNA mutations and neuromuscular disease

Mitochondrial DNA mutations have been identified in patients with certain neuromuscular diseases. Point mutations have been associated with maternally inherited diseases, while deletions have been identified in some 'spontaneous' cases.     

Neurodegenerative Erkrankungen des Kindesalters

The understanding of neurodegenerative diseases of childhood has been changing rapidly in recent times: not only is the number of different diseases and underlying genetic defects steadily increasing, approaches to diagnosis and treatment have also developed because of recent technological and therapeutic advances relating to this group of disorders. New gene defects have been identified that provide a basis for understanding the molecular mechanisms underlying this group of diseases, and for the development of targeted therapies. This review focuses predominantly on one of the most common groups of diseases leading to degeneration of the central nervous system, neuronal ceroid lipofuscinosis (NCL). The number of NCL-causing genes and knowledge about genotype–phenotype correlations has been growing over the past few years and the first therapies have been developed. Hence, this group of diseases represents the rapid scientific development in the field of rare neurodegenerative diseases in childhood very well.     

Polyglutamine-mediated neurodegeneration: Use of chaperones as prevention strategy

Polyglutamine diseases are a class of inherited neurodegenerative disorders caused by the expansion of a polyglutamine tract within the respective proteins. Clinical studies have revealed that the forming of neuronal intranuclear inclusions by the disease protein is a common pathological feature of polyglutamine diseases. Although there has been considerable progress in understanding polyglutamine diseases, many questions regarding their mechanism are still unanswered. The finding that molecular chaperones are associated with ubiquitinated intranuclear inclusions clearly indicates a crucial role of molecular chaperones in the generation of these fatal diseases. Molecular and chemical chaperones have been found to be a good agent for suppressing many polyglutamine diseases in several animal models. In this review, I discuss the roles of the ubiquitin-proteasome pathway and molecular chaperones in the development of polyglutamine diseases and probable approach for the prevention of many of these fatal disorders using molecular chaperones as a therapeutic agent. Newly found chemical chaperones have been demonstrated to be potentially useful and could be used as a therapeutic strategy in preventing many versions of polyglutamine diseases.     

Evaluation of candidate genes in the absence of positional information: a poor bet on a blind dog!

More than 350 inherited diseases have been reported in dogs and at least 50% of them have human counterparts. To remove the diseases from dog breeds and to identify canine models for human diseases, it is necessary to find the mutations underlying them. To this end, two methods have been used: the functional candidate gene approach and linkage analysis. Here we present an evaluation of these in canine retinal diseases, which have been the subject of a large number of molecular genetic studies, and we show the contrasting outcomes of these approaches when dealing with genetically heterogeneous diseases. The candidate gene approach has led to 377 published results with 23 genes. Most of the results (66.6%) excluded the presence of a mutation in a gene or its coding region, while only 3.4% of the results identified the mutation causing the disease. On the other hand, five linkage analysis studies have been done on retinal diseases, resulting in three identified mutations and two mapped disease loci. Mapping studies have relied on dog research colonies. If this favorable application of linkage analysis can be extended to dogs in the pet population, success in identifying canine mutations could increase, with advantages to veterinary and human medicine.     

Understanding hereditary diseases using the dog and human as companion model systems

Animal models are requisite for genetic dissection of, and improved treatment regimens for, human hereditary diseases. While several animals have been used in academic and industrial research, the primary model for dissection of hereditary diseases has been the many strains of the laboratory mouse. However, given its greater (than the mouse) genetic similarity to the human, high number of naturally occurring hereditary diseases, unique population structure, and the availability of the complete genome sequence, the purebred dog has emerged as a powerful model for study of diseases. The major advantage the dog provides is that it is afflicted with approximately 450 hereditary diseases, about half of which have remarkable clinical similarities to corresponding diseases of the human. In addition, humankind has a strong desire to cure diseases of the dog so these two facts make the dog an ideal clinical and genetic model. This review highlights several of these shared hereditary diseases. Specifically, the canine models discussed herein have played important roles in identification of causative genes and/or have been utilized in novel therapeutic approaches of interest to the dog and human.     

Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies

Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20?years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision.     

Retroviruses and nervous system disease.

During the past decade retroviruses have been recognized as causes of human neurological disease. A wide clinical spectrum of neurological and neuromuscular diseases have been reported with HIV infections, and studies of these diseases have raised novel and exciting hypotheses of pathogenesis. As yet the full clinical spectrum of diseases associated with HTLV-1 has yet to be defined, and the pathogenesis of the chronic spastic paraparesis remains a mystery. Chronic neurological diseases in animals caused by both oncoviruses and lentiviruses can provide some clues to the pathogenesis of these newly recognized human neurological illnesses.     

Coral diseases: what is really known?

Reports of new and emerging coral diseases have proliferated in recent years. Such coral diseases are often cited as contributing to coral reef decline. Many of these diseases, however, have been described solely on the basis of field characteristics, and in some instances there is disagreement as to whether an observed coral condition is actually a disease. A disease pathogen has been identified for only three coral diseases, and for only two of these has the pathogen been shown (in the laboratory) to be the disease agent. In one case, the same disease name has been used for several widely varying coral syndromes, whereas in another multiple disease names have been applied to symptoms that may be caused by a single disease. Despite the current confusion, rapid progress is being made.     

珊瑚疾病的主要类型、生态危害及其与环境的关系

与人和其它动物一样,珊瑚也生病。在过去30多年里各种珊瑚疾病对全球珊瑚礁造成了严重破坏。目前已知的珊瑚疾病多达30多种,但确定病原体的仅6种。阐述了造礁石珊瑚的7种最主要疾病类型(黑带病、黑斑病、白带病、白色瘟疫、白斑病、黄带病和珊瑚白化病等)的症状、扩散速率、疾病患病率、珊瑚死亡率等。频繁发生的珊瑚疾病导致主要造礁物种死亡,减少礁区的生物多样性,对珊瑚礁生态系统产生破坏日益严重,甚至引起以珊瑚为主导的珊瑚礁系统转变为以大型藻类为主导的生态系统。全球气温上升和人为活动引起的一系列环境因子的变化被认为是各种珊瑚疾病发生的诱导因素,海水温度升高是Oculina patagonica和Pocillopora damicornis2种珊瑚细菌性白化的先决条件,其它环境因素如营养盐、有机污染物等超过一定量或pH值改变时会对珊瑚造成生理压力,降低其对病毒的抵抗力,也可能改变病原体生存的生态阈值,增强其病原毒力,引发并加速疾病的扩散。此外,珊瑚的生存环境如覆盖度、水深等与疾病的爆发也有一定的关系,一般认为覆盖度高,水深较浅处珊瑚疾病发生频率高。     

Cracks in the foundation: keratin filaments and genetic disease

In the past three years, defects in the genes that encode intermediate filament (IF) proteins have been found to be responsible for some inherited skin diseases, and others have been implicated in certain motor neuron diseases and cardiomyopathies. This article reviews how knowledge of IF structure led to the discovery of genetic disorders of IFs, and how the clinical manifestations of these diseases have confirmed the notion that IFs provide the mechanical strength of cells.     

Age related mitochondrial degenerative disorders in humans

Disorders caused by mitochondrial respiratory chain deficiency due to mutations in mitochondrial DNA have varied phenotypes but many involve neurological features often associated with cell loss within specific brain regions. These disorders, along with the increasing evidence of decline in mitochondrial function with ageing, have raised speculation that primary changes in mitochondria could have an important role in age-related neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Evidence supporting a role for mitochondria in common neurodegenerative diseases comes from studies with the toxin MPP+ and familial PD, which has been shown to involve proteins such as DJ-1 and Pink1 (both of which are predicted to have a role in mitochondrial function and oxidative stress). Mutations within the mitochondrial genome have been shown to accumulate with age and in common neurodegenerative diseases. Mitochondrial DNA haplogroups have also been shown to be associated with certain neurodegenerative conditions. This review covers the primary mitochondrial diseases but also discuss the potential role of mitochondria and mitochondrial DNA mutations in mitochondrial and neurodegenerative diseases, in particular in PD and in AD.     

Relationships between single nucleotide polymorphisms of antioxidant enzymes and disease

The presence and progression of numerous diseases have been linked to deficiencies in antioxidant systems. The relationships between single nucleotide polymorphisms (SNPs) arising from specific antioxidant enzymes and diseases associated with elevated oxidative stress have been studied with the rationale that they may be useful in screening for diseases. The purpose of this narrative review is to analyse evidence from these studies. The antioxidant enzyme SNPs selected for analysis are based on those most frequently investigated in relation to diseases in humans: superoxide dismutase (SOD2) Ala16Val (80 studies), glutathione peroxidise (GPx1) Pro197Leu (24 studies) and catalase C-262T (22 studies). Although the majority of evidence supports associations between the SOD2 Ala16Val SNP and diseases such as breast, prostate and lung cancers, diabetes and cardiovascular disease, the presence of the SOD2 Ala16Val SNP confers only a small, clinically insignificant reduction (if any) in the risk of these diseases. Other diseases such as bladder cancer, liver disease, nervous system pathologies and asthma have not been consistently related to this SOD SNP genotype. The GPx1 Pro197Leu and catalase C-262T SNP genotypes have been associated with breast cancer, but only in a small number of studies. Thus, currently available evidence suggests antioxidant enzyme SNP genotypes are not useful for screening for diseases in humans.     

Inhibitors of dihydrofolate reductase in Leishmania and trypanosomes

The protozoan diseases leishmaniasis, Chagas' disease and African trypanosomiasis are major health problems in many countries, particularly developing countries, and there are few drugs available to treat these diseases. Dihydrofolate reductase (DHFR) inhibitors have been used successfully in the treatment of a number of other diseases such as cancer, malaria and bacterial infections; however they have not been used for the treatment of these diseases. This article summarises studies on leishmanial and trypanosomal DHFR inhibitor development and evaluation. Possible mechanisms of resistance to DHFR inhibitors are also discussed.     

THERPA: A small molecule database related to prion protein regulation and prion diseases progression

Prion diseases are fatal neurodegenerative disorders that affect humans and animals. Although various small molecules have been evaluated for application in the treatment of prion diseases, none have been shown to be efficacious. Expanding our knowledge of these molecules is important for understanding of the complex mechanisms of prion diseases. To improve access to the scattered information on small molecules related to prion diseases, we built a database of therapeutic molecules associated with prion diseases (THERPA, therpa.pythonanywhere.com). THERPA includes 119 small molecules and their 283 relationships with prion diseases. THERPA is an interactive visual database and useful for improving search efficiency which can help researchers identify intrinsic small molecules that can be used for developing therapeutics for prion diseases.     

Molecular aspects of the etiopathogenesis of the parathyroid gland diseases

Current views on the molecular aspects of familial parathyroid gland diseases have been presented (familial primary hyperparathyroidism, hypoparathyroidism and psuedohypoparathyroidism). Their inherited mode and genetic abnormalities have been described. Particularly, the following genes: HRPT2, MEN1, RET, CASR, GNAS have been shown. Localization, structure, expression and structural changes (mutations) found in patients with familial parathyroid gland diseases have been presented. Attention has been paid to clinical and histopathologic symptoms, which should indicate the need to undertake genetic studies.     

Fingerprinting the diseased prostate: associations between BPH and prostate cancer

Two of the most common diseases which occur in ageing men relate to their prostate. BPH and prostate cancer are prevalent diseases which have an impact on most men as they age. The advent of gene expression analysis has provided an opportunity to examine these diseases in a novel fashion. These analyses, to date, have revealed associations between these two diseases which have not been previously identified. These commonalities include global genetic changes which occur throughout the prostates in individuals with these diseases. Understanding the fingerprints of these diseases is providing novel markers and treatment strategies for both BPH and prostate cancer.     

Diamine derivatives with antiparasitic activities

There are a lack of effective chemotherapies for many parasitic diseases. Polyamine pathways have been reported as potential targets for the development of new chemotherapies against parasitic diseases. In the present study, different libraries of substituted diamines totalling 78 compounds have been synthesized on solid support and their activities against malaria and leishmania parasites have been determined. Most active compounds demonstrated submicromolar activities against both organisms and their structure-activity relationships are discussed.     

The classification of streptococci and human streptococcal diseases

The modern nomenclature, phenotypic, medical, ecological and phylogenetic classification of streptococci and different classification of streptococcal human diseases are presented. All phylogenetic groups of streptococci have been shown to contain species causing diseases in man. The most medically significant groups are the phylogenetic groups Pyogenes and Mitis. Directions of the improvement of the classification of streptococci and streptococcal human diseases on the basis of modern concepts on the taxonomy of streptococci, the biological properties and ecology of the infective agents, as well as the genesis and clinical picture of diseases induced by them, have been determined.     

Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases

Progeroid syndromes have been the focus of intense research in part because they might provide a window into the pathology of normal ageing. Werner syndrome and Hutchinson-Gilford progeria syndrome are two of the best characterized human progeroid diseases. Mutated genes that are associated with these syndromes have been identified, mouse models of disease have been developed, and molecular studies have implicated decreased cell proliferation and altered DNA-damage responses as common causal mechanisms in the pathogenesis of both diseases.