毒性T细胞抗原4功能性遗传多态与儿童哮喘发病风险的关系

目的毒性T细胞抗原4（cytotoxic T-lymphocyte antigen-4,CTLA-4）是细胞免疫调控过程中的关键因子,在哮喘发病过程中起重要作用。本研究探讨CTLA-4编码区遗传多态＋49 G〉A单核苷酸多态与深圳地区儿童哮喘遗传易感性的关系。方法以聚合酶链反应（PCR）和限制性片段长度多态性（restriction fragment length polymorphism,RFLP）分析方法,检测了118例哮喘患儿和160例正常对照者CTLA-4＋49 G〉A基因型,比较不同基因型与哮喘发病风险的关系。结果 CTLA-4＋49 A等位基因频率在哮喘患儿和正常对照中的分布有显著性差异（32.6%vs 24.7%,P=0.039）。CTLA-4三种基因型GG、GA和AA在病例和对照组中的分布有统计学显著性差异（P=0.031,趋势检验）,携带CTLA-4 AA或GA基因型者罹患哮喘的风险是GG基因型携带者的1.62倍（95%CI,0.95-2.68,P=0.05）。结论 CTLA-4单核苷酸多态＋49 G〉A可能是我国儿童哮喘的遗传易感因素。     

Studies on the hippocampal formation: From basic development to clinical applications: Studies on schizophrenia

The hippocampal formation plays a critical role in cognitive function. The developmental events that shape the hippocampal formation are continuing to be elucidated and their implications for brain function are emerging as well as applying those advances to interventions that have important possibilities for the treatment of brain dysfunction. The story told in this chapter is about the use of the in oculo transplant method to illuminate intrinsic and extrinsic features that underlie the development of the dentate gyrus and adjacent hippocampus and the role of one molecule in the hippocampus and schizophrenia. Schizophrenia, originally conceptualized as a dysfunction in dopaminergic neurotransmission, is now known to involve multiple neuronal systems. Dysfunction of hippocampal neurons is emerging as one of its signature pathological features. Basic insights into the development and function of hippocampal interneurons form the basis of a new treatment initiative for this illness. Evidence for the role of the alpha 7-nicotinic acetylcholine receptor in the development and function of these neurons in rodents has led to human trials of nicotinic agonists for cognitive dysfunction in schizophrenia and the possibility of improving hippocampal development in children at risk for schizophrenia by perinatal supplementation with choline, which can act as an alpha 7-nicotinic acetylcholine receptor agonist.     

Retino-hypothalamic-pineal hypothesis in the pathophysiology of primary headaches

Primary headaches include migraine, tension, cluster headaches, paroxysmal hemicrania and miscellaneous headaches unassociated with structural lesions. A putative role of the retino-hypothalamic-pineal (RHP) axis in the pathophysiology of primary headaches is reviewed in terms of (1) retinal dysfunction, (2) hypothalamic dysfunction and human circadian desynchrony, (3) pineal melatonin dysfunction and (4) rostral limbic dysfunction mediating the human stress response. Unified RHP hypothesis is proposed, suggesting that an acute, periodic or chronic, circadian desynchrony and dysfunction of the whole or part of the RHP axis is implicated in the pathophysiology of primary headaches. Supportive evidence for the RHP hypothesis, including recent PET studies showing changes in dorsal pons, hypothalamus and rostral limbic structures, is presented.     

Genetic predisposition to leprosy: A major gene reveals novel pathways of immunity to Mycobacterium leprae

The elucidation of the genetic control of susceptibility to common infectious diseases is expected to provide new and more effective tools for prevention and control of some of the most pressings health needs on a global scale. A major advantage of whole genome based genetic approaches is that no a priori assumptions about mechanisms of pathogenesis need to be made in these studies. Hence, genetic studies can identify previously unrecognized pathways of disease susceptibility and tag critical pathogenic events for further biochemical, immunological or physiological analysis. We have applied this strategy to leprosy, a disease that still claims 400,000 new cases each year. We identified genetic variants in the shared promoter region of the PARK2 and PACRG genes as major risk factors of leprosy susceptibility. Both encoded proteins are part of the cellular ubiquitination system. Specifically, PARK2, the cause of early onset Parkinson's disease, is an E3 ligase that likely is involved in controlled proteolysis, the cellular anti-oxidants response and the regulation of innate immune responsiveness. In addition, numerous E3 ligases have recently been shown to be critical regulators of immunity. While the specific role of PARK2/PACRG in leprosy pathogenesis remains unknown, a number of experimentally testable scenarios can be developed to further explore the role of these proteins in anti-Mycobacterium leprae host responsiveness.     

三态MVR-PCR方法检测中国汉族人群D2S44(YNH24)基因座3'端遗传多态性

目的 揭示中国汉族人群（河北）D2S44基因座3′端的遗传多态性。方法 采用三态MVR-PCR和变性PAGE-银染技术对D2S44基因座进行检测，结果用数字编码表示。结果 在被检116名无关个体中，每一个体平均得到11个数字编码，未发现任何两个无关个体所有编码相同，三种重复单位出现的频率分别为：Ⅰ型：34.33%，Ⅱ型：33.52%，Ⅲ型：21.63%，0型：10.51%。在116名无关个体中，两个无关个体拥有相同的编码概率为0.1365，所有个体11个编码均相同的概率为3.06×10-10，杂合度为0.9755，多态信息含量为0.9751，非父排除率为0.9510。结论D2S44基因座在中国汉族人群（河北）中具有很高的遗传多态性，在人类群体遗传学及法医学研究领域有重要应用价值。     

Human growth hormone 1 (GH1) gene expression: complex haplotype-dependent influence of polymorphic variation in the proximal promoter and locus control region

The proximal promoter region of the human pituitary expressed growth hormone (GH1) gene is highly polymorphic, containing at least 15 single nucleotide polymorphisms (SNPs). This variation is manifest in 40 different haplotypes, the high diversity being explicable in terms of gene conversion, recurrent mutation, and selection. Functional analysis showed that 12 haplotypes were associated with a significantly reduced level of reporter gene expression whereas 10 haplotypes were associated with a significantly increased level. The former tend to be more prevalent in the general population than the latter (p<0.01), possibly as a consequence of selection. Although individual SNPs contributed to promoter strength in a highly interactive and non-additive fashion, haplotype partitioning was successful in identifying six SNPs as major determinants of GH1 gene expression. The prediction and functional testing of hitherto unobserved super-maximal and sub-minimal promoter haplotypes was then used to test the efficacy of the haplotype partitioning approach. Electrophoretic mobility shift assays demonstrated that five SNP sites exhibit allele-specific protein binding. An association was noted between adult height and the mean in vitro expression value corresponding to an individual's GH1 promoter haplotype combination (p=0.028) although only 3.3% of the variance of adult height was found to be explicable by reference to this parameter. Three additional SNPs, identified within sites I and II of the upstream locus control region (LCR), were ascribed to three distinct LCR haplotypes. A series of LCR-GH1 proximal promoter constructs were used to demonstrate that 1) the LCR enhanced proximal promoter activity by up to 2.8-fold depending upon proximal promoter haplotype, and that 2) the activity of a given proximal promoter haplotype was also differentially enhanced by different LCR haplotypes. The genetic basis of inter-individual differences in GH1 gene expression thus appears to be extremely complex.     

Genetic Analysis of FAM46A in Spanish Families with Autosomal Recessive Retinitis Pigmentosa: Characterisation of Novel VNTRs

Retinitis pigmentosa (RP) is a group of retinal dystrophies characterised primarily by rod photoreceptor cell degeneration. Exhibiting great clinical and genetic heterogeneity, RP be inherited as an autosomal dominant (ad) and recessive (ar), X-linked (xl) and digenic disorder. RP25 , a locus for arRP, was mapped to chromosome 6p12.1-q14.1 where several retinal dystrophy loci are located. A gene expressed in the retina, FAM46A , mapped within the RP25 locus, and computational data revealed its involvement in retinal signalling pathways. Therefore, we chose to perform molecular evaluation of this gene as a good candidate in arRP families linked to the RP25 interval. A comprehensive bioinformatic and retinal tissue expression characterisation of FAM46A was performed, together with mutation screening of seven RP25 families.
Herein we present 4 novel sequence variants, of which one is a novel deletion within a low complexity region close to the initiation codon of FAM46A . Furthermore, we have characterised for the first time a coding tandem variation in the Caucasian population.
This study reports on bioinformatic and moleculardata for the FAM46A gene that may give a wider insight into the putative function of this gene and its pathologic relevance to RP25 and other retinal diseases mapping within the 6q chromosomal interval.     

Polymorphisms of the prion protein gene in sheep of Inner Mongolia,China

Polymorphisms of the prion protein gene (Prnp), especially the amino acid residue alterations at codons 136, 154, and 174, in sheep have been found to be associated with susceptibility to scrapie disease. We investigated Prnp polymorphisms in three local sheep breeds in Inner Mongolia, China. Blood samples were collected from 46 Ujumqin, 34 Sunite, and 22 Mongolian sheep. The genetic DNA of blood samples was extracted, amplified and sequenced, and amino acid alignment was determined. Polymorphisms were detected at 8 codons, among which M157I, Q220H, and R223K have not been previously reported. The frequency of the amino acid residues ARQ/ARQ at codons 136, 154, and 171, respectively, which is associated with medium-high susceptibility to scrapie, was 74.5%, and the frequency of scrapie-resistant genotype ARR/ARR was 7.9%. The highly susceptible genotype VRQ/VRQ at these codons as not detected from the tested sheep. Of the three sheep breeds, Ujumqin sheep had the highest frequency (15.2%) of scrapie-resistant amino acid sequence, ARR/ARR at codons 136, 154, and 171, respectively, accounting for 87.5% sheep that carry these polymorphisms. Our findings are of special importance for both live sheep export and sheep breeding.