Trisomy-driven overexpression of DYRK1A kinase in the brain of subjects with Down syndrome

Down syndrome (DS) is the most common genetic disorder associated with mental retardation (MR). It is believed that many of the phenotypic features of DS stem from enhanced expression of a set of genes located within the triplicated region on chromosome 21. Among those genes is DYRK1A encoding dual-specificity proline-directed serine/treonine kinase, which, as documented by animal studies, can potentially contribute to cognitive deficits in DS. Whether this contribution can be exerted through elevated levels of DYRK1A protein in the brain of DS subjects was the main goal of the present study. The levels of DYRK1A protein were measured by Western blotting in six brain structures that included cerebral and cerebellar cortices and white matter. The study involved large cohorts of DS subjects and age-matched controls representing infants and adults of different age, gender and ethnicity. Trisomic Ts65Dn mice, an animal model of DS, were also included in the study. Both in trisomic mice and in DS subjects, the brain levels of DYRK1A protein were increased approximately 1.5-fold, indicating that this protein is overexpressed in gene dosage-dependent manner. The exception was an infant group, in which there was no enhancement suggesting the existence of a developmentally regulated mechanism. We found DYRK1A to be present in every analyzed structure irrespective of age. This widespread occurrence and constitutive expression of DYRK1A in adult brain suggest an important, but diverse from developmental role played by this kinase in adult central nervous system. It also implies that overexpression of DYRK1A in DS may be potentially relevant to MR status of these individuals during their entire life span.     

孕妇血清ADAM12-S水平与妊娠结局的相关性研究

目的探讨妊娠早期孕妇血清解整合素-金属蛋白质酶12（ADAM12-S）水平变化与唐氏综合征等妊娠结局的关系。方法应用时间分辨荧光免疫分析法检测早孕期（8-11周）孕妇血清中ADAM12-S水平,并分析ADAM12-S水平变化与唐氏综合征等妊娠结局的关系。结果正常单胎血清ADAM12-S水平随孕周增加而逐渐上升的趋势,且呈线性相关（r=0.993,P〈0.01）。唐氏综合征等非整倍体染色体异常的ADAM12-S水平的明显低于正常单胎孕妇,差异有统计学意义（P〈0.05）.结论早孕期孕妇血清中ADAM12-S水平随孕周增加而上升,可用于非整倍体常染色体异常的筛查,预测胎停育、异位妊娠等早期妊娠丢失,可作为产前筛查指标。     

Review of Dscam-mediated immunity in shrimp and other arthropods

Although true adaptive immunity is only found in vertebrates, there is increasing evidence that shrimp and other arthropods exhibit immune specificity and immune memory. The invertebrate immune response is now called “innate immunity with specificity” or “immune priming”, and its underlying mechanisms are still unclear. However, while vertebrate antibodies have no invertebrate homolog, the Down syndrome cell adhesion molecule (Dscam), which is a hypervariable protein created by alternative splicing, can function as a pathogen-specific recognizing molecule in arthropods. Here we review our current understanding of the Dscam-mediated immune responses in arthropods, especially in shrimp, and show that Dscam may be involved in both general innate immunity and the pathogen-specific immune response.     

应用定量PCR方法快速基因诊断Down综合征

目的 探讨用定量聚合酶链反应方法对Down综合征进行基因诊断。 方法 以短串联重复序列（D21S11）作为遗传标记,合成特异引物,用同位素标记聚合酶链反应扩增后对11名正常人（6例外周血,5例羊水）及28例Down综合征患者（外周血）进行定量检测。 结果 11名正常人中10人出现DNA含量为1：1关系的2条电泳带,1人为1条带。28例患者中24人出现DNA含量2：1的2条带,3人为DNA含量为1：1：1的3条带,1人为1条带。 结论 D21S11位点短串联重复序列多态是对Down综合征基因诊断很有应用价值的遗传标记,应用定量聚合酶链反应方法可在24小时内对Down综合征做出快速、准确的产前及临床基因诊断。     

Functional Analysis of Genes Implicated in Down Syndrome: 2. Laterality and Corpus Callosum Size in Mice Transpolygenic for Down Syndrome Chromosomal Region −1 (DCR-1)

The association between atypical laterality and mental retardation has been reported several times, particularly in Down syndrome (DS). We investigated common genetic correlates of these components of the syndrome, examining direction (number of right paw entries in the Collins test) and degree (absolute difference between the number of right paw entries and the number of left paw entries) in mice that had incorporated extra-contiguous HSA21 fragments covering DCR-1 (Down Chromosomal Region-1). As corpus callosum size is substantially reduced in DS, and as the structure has been suspected of playing a role in atypical laterality, we also measured the corpus callosum in these mice. Extra copies of two regions (F7 and E6) have been associated with an atypical degree of laterality (strongly reduced degree). Extra copies of E8, G6 and E6 are also linked to the reduced size of the corpus callosum, indicating that the abnormal number of fibers linking the two hemispheres is not associated with atypical laterality in DS. Together, these results indicate that some of the genes involved in atypical laterality and in the reduced size of the corpus callosum in DS are present on DCR-1. An extra copy of F7 and, to a lesser extent, an extra copy of E6, are also associated with cognitive impairment. These results support the hypothesis of common genetic correlates in atypical laterality and mental retardation in DS.     

Audiovisual information affects informed choice and experience of information in antenatal Down syndrome screening--a randomized controlled trial

Objective

To evaluate the effects of an information film on making an informed choice regarding Down syndrome screening, and women's knowledge and experiences of information.

Methods

Randomized controlled trial including 184 women in the intervention group and 206 controls recruited from maternity units in Stockholm, Sweden. The intervention was an information film presented as a complement to written and verbal information. Data were collected via a questionnaire in gestational week 27. Three different measures were combined to measure informed choice: attitudes towards Down syndrome screening, knowledge about Down syndrome and Down syndrome screening, and uptake of CUB (combined ultrasound and biochemical screening).

Results

In the intervention group 71.5% made an informed choice versus 62.4% in the control group. Women in the intervention group had significantly increased knowledge, and to a greater extent than the control group, experienced the information as being sufficient, comprehensible, and correct.

Conclusions

An information film tended to increase the number of women who made an informed choice about Down syndrome screening. Participants were more satisfied with the information received.

Practice implications

Access to correct, nondirective, and sufficient information is essential when making a choice about prenatal diagnostics. It is essential with equivalent information to all women.     

Down syndrome as a model of DNA polymerase beta haploinsufficiency and accelerated aging

Down syndrome is a condition of intellectual disability characterized by accelerated aging. As with other aging syndromes, evidence accumulated over the past several decades points to a DNA repair defect inherent in Down syndrome. This evidence has led us to suggest that Down syndrome results in reduced DNA base excision repair (BER) capacity, and that this contributes to the genomic instability and the aging phenotype of Down syndrome. We propose important roles for microRNA and/or folate metabolism and oxidative stress in the dysregulation of BER in Down syndrome. Further, we suggest these pathways are involved in the leukemogenesis of Down syndrome. We have reviewed the role of BER in the processing of oxidative stress, and the impact of folate depletion on BER capacity. Further, we have reviewed the role that loss of BER, specifically DNA polymerase beta, plays in accelerating the rate of aging. Like that seen in the DNA polymerase beta heterozygous mouse, the aging phenotype of Down syndrome is subtle, unlike the aging phenotypes seen in the classical progeroid syndromes and mouse models of aging. As such, Down syndrome may provide a model for elucidating some of the basic mechanisms of aging.     

Micronucleated lymphocytes in parents of Down syndrome children

Down syndrome (DS) is the most common disease due to an autosomal aneuploidy in live born children and also the major known genetic cause of mental retardation. The risk of a DS pregnancy increases substantially with increasing maternal age. However, several women aged less than 35 years at conception have a child with DS. The micronucleus (MN) assay can identify chromosome breakage or chromosome malsegregation and is an ideal biomarker to investigate genomic instability. The aim of the present study was to determine the frequency of peripheral lymphocytes with MN in the parents of DS individuals. The subjects were 17 couples, 1 father and 9 mothers, and 24 couples who had at least one healthy child formed the control group. For each individual we evaluated the frequency of binucleated micronucleated lymphocytes (BNMN%) as number of binucleated lymphocytes containing one or more MN per 1000 binucleated cells. The mean age of DS parents and controls was 32.6 and 29.8 years, respectively. The frequency of MN in DS parents was significantly higher compared to controls. The higher frequency of MN in DS parents suggests a higher predisposition of DS parents to aneuploidy events in this sample.     

一例伴 GATA1基因新突变的唐氏综合征患儿的临床及实验室分析

目的 分析1例唐氏综合征(Down syndrome,DS)相关髓系增殖患儿的临床及实验学特征。 方法 对患儿的临床特点及外周血细胞形态学、荧光原位杂交及免疫学分型等实验室检查结果进行分析,对114种血液肿瘤相关基因进行高通量测序分析。 结果 患儿肝功能及凝血功能明显异常,贫血,白细胞计数偏高,外周血原始细胞的比例明显增高,形态学染色及免疫学分型支持巨核细胞系增殖的特点,荧光原位杂交显示为21三体。114种白血病相关基因的外显子测序显示,仅 GATA1基因的第2外显子存在突变(c.220＋2dupT),突变率为95.8%,且为新的突变类型,未见其余所测基因的突变。 结论 患儿患有DS,并伴有 GATA1基因的突变。其外周血出现原始细胞增多,应考虑为一过性骨髓异常增生,有别于先天性白血病。     

Del(X) (q26) in a phenotypically normal woman and her daughter who also has trisomy 21

We present a phenotypically normal woman with del(X)(q26) with no evidence of mosaicism, who had two pregnancies resulting in two live-born infants. Her first child had trisomy 21 Down syndrome and the del(X)(q26). To our knowledge, this woman is the first known case of presumably nonmosaic del(Xq) producing live-born infants. This finding can be explained on the basis of persistence into adulthood of germ cells in ovaries of the rare del(Xq) individuals. The normal phenotype in this woman supports the hypothesis that the absence of genes of middle Xq segment.(q13 → q26) is responsible for the somatic manifestations of the Ullrich-Turner syndrome. Our finding suggests that prenatal diagnosis should be offered not only to pregnant women with numerical X chromosome abnormalities, as suggested previously, but also to those with structural X chromosome abnormalities, because of the possibility of chromosome aberrations in the offspring of such women.     

孕中期母血产前筛查先天缺陷的研究

目的评价孕中期AFP和游离βHCG二联生化指标在产前筛查中的实用价值。方法应用时间分辨荧光免疫检测技术对3384例孕15~20w孕妇外周血AFP和游离βHCG二联生化指标进行检测,检测结果应用Multicalc软件计算出唐氏综合征、神经管畸形、爱得华综合征等三种先天缺陷的风险率,高风险孕妇建议B超、羊水或脐血培养明确诊断,产后随访证实。结果产前筛查3384例孕妇,筛查出高危孕妇177例,阳性率为4.3%,其中唐氏高风险131例,18三体高风险7例,神经管畸形高风险21例。高危孕妇行羊水培养133例,发现异常核型6例。B超证实胎儿畸形10例。结论孕中期生化二联指标是产前筛查异常胎儿的有效指标,遵循产前诊断规定的条件下,值得推广应用。     

唐氏综合征患儿线粒体基因组突变的分析

目的 研究唐氏综合征中线粒体DNA突变情况.方法 采用高通量测序和焦磷酸测序检测7个唐氏综合征(Down's syndrome,DS)家系中的患儿和母亲的线粒体基因组序列,分析线粒体基因组序列的变化情况.结果 ①DS患儿中检测到36个与其母亲中不同的线粒体DNA突变,其中14个位点是首次在唐氏综合征样本中发现;②36个线粒体DNA突变主要发生于D-Loop区和线粒体复合物Ⅰ中;③ 线粒体基因组13个编码基因中,有11个基因检测到线粒体DNA的突变;④ 焦磷酸测序对线粒体基因组杂合突变频率的检测结果和高通量测序结果吻合.结论 DS患儿中广泛存在线粒体DNA的突变,这些突变可能与唐氏综合征的线粒体功能异常相关.     

孕中期唐氏综合征风险估计新模型的初步建立

目的建立一种新的孕中期唐氏综合征风险估计模型,以提高孕中期唐氏综合征产前筛查的效率。方法根据一般孕妇群体与唐氏综合征妊娠孕妇群体AFP MoM值和Free-β-hCG的MoM值分布的不同建立风险估计模型,并与现有模型进行接受者工作曲线（Receiver Operation Curve,ROC）分析比较。结果新孕中期唐氏综合征风险估计模型筛查效率较现有模型有明显提高。结论新孕中期唐氏综合征风险估计模型筛查效率较现有模型有明显提高,该模型值得今后进一步实验验证及优化。