基于脾肾两脏探讨脑常染色体显性动脉病变伴皮层下梗死和白质脑病的研究思路

脑常染色体显性动脉病变伴皮层下梗死和白质脑病(Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy,CADASIL),是一种非动脉硬化性、非淀粉样变形的基因遗传性脑血管疾病,其临床主要表现为头痛、认知功能减退、精神异常等症状。目前公认此病是由Notch3基因突变导致平滑肌细胞退行性病变,只能对症治疗,没有特色疗法能够治愈。中医学认为本病的病位在脑,病因可责之于脾肾两脏。肾中所藏之精为脏腑阴阳的根本,其依赖于后天水谷精微充养,方能生生不息而不致匮乏;而后天的脾之精气有赖于肾中精气对脾气及脾阴脾阳的推动和资助,才能不断地化生,以输布全身,营养脏腑及形体官窍。根据脾肾相关理论也系统阐述了脾肾两脏在生理及病理上的互相影响的关系。肾为先天之本,肾中精气的盛衰影响着子代的先天禀赋与生长发育,与遗传物质关系密切;脾为后天之本,脾之精气来源于水谷精微,其功能易受饮食、环境影响,与基因遗传机制有一定关联。本文主要从中医角度论述CADASIL与脾肾两脏的关系以及通过对其病理机制的研究,也提出了先后天之本与本病的自然病程的渐进性是相关的,以及健脾固肾法在治疗过程中是必不可少的,为CADASIL的治疗也提供了新的治疗方向。

常染色体显性遗传玻璃体视网膜脉络膜病变一家系的致病基因筛查及临床分析

目的使用外显子结合目标区域捕获测序检测常染色体显性遗传玻璃体视网膜脉络膜病变(autosomal dominant vitreoretinochoroidopathy,ADVIRC)家系的致病基因,并分析其临床表型。方法收集重庆地区常染色体显性遗传玻璃体视网膜脉络膜病变先证者及4代成员的临床资料,完善眼科检查。采集该家系4例患者及8例健康成员的外周静脉血,提取基因组DNA,运用外显子结合目标区域捕获测序芯片进行测序,并对测序结果进行分析后得到候选致病基因性突变位点。运用PCR和直接测序进行验证,确定致病基因。根据致病基因的临床表型对该家系进行临床分析。结果基因检测发现第六外显子的杂合突变BEST1(c.704TR>C),家系患者中出现的小角膜、先天性白内障、周边视网膜脉络膜发育不良、晚期易发生青光眼等符合该突变基因的临床表型。结论 BEST1基因的c.704TR>C杂合突变为该ADVIRC家系的致病基因之一。

遗传性视神经病变患者临床表型及基因检测多态性分析—单中心队列研究

目的分析临床常见遗传性视神经病变(HON)患者基因突变的基因型及临床表现的多样性。方法2013年5月~2021年10月本院神经眼科中心纳入的拟诊遗传性视神经病变患者,经二代基因测序分析与疾病相关的线粒体环状DNA基因突变,并进行多态性分析。结果537例拟诊HON患者,其中遗传性视网膜病变88例(16.4%)、视神经病变449例(83.6%)。完成基因检测者375例,阳性率为66.4%(249/375)。249例基因检测阳性患者中男女比为3.7∶1,以40岁以下的儿童及青少年为主。其中主要致病基因突变为线粒体环基因点突变导致的Leber遗传性视神经病变(LHON)及核基因OPA1突变导致的显性遗传性视神经病变(DOA)。在103例LHON阳性样本中检测出线粒体chrM-11778 G>A突变,占41.4%;其他特殊线粒体点突变有3291、8344、13413等。发现罕见基因突变包括OPA3、WSF1、CISD2、DNM1L、ACO2、AFG3L2、SPG7、NDUFS2、FGFR2、BBS10、TUBA8、NBAS、RAB18等,均与视神经萎缩相关。结论临床拟诊HON及不明原因的视神经萎缩患者中,线粒体相关的遗传性疾病占比高。这类患者通过有针对性的基因检测技术可以最大限度明确潜在的突变位点及多态性,为精准医疗及基因治疗奠定基础。

The Gene of Megalencephalic Leukoencephalopathy with Subcortical Cysts is Mapped on Chromosome 22q13.3 with 250 kb Interval

Objective: Vacuolating megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a recently described syndrome with autosomal recessive mode of inheritance. Its possible gene was located on chromosomal 22q tel with 3-cM. The purpose of this study was to narrow down the genetical distance on chromosomal 22q tel with MLC. Methods: Thirty-nine MLC patients in 33 families were collected,and the linkage analysis and haplotype analysis of twelve informative families were done, using seven microsatellite markers and four SNP markers. Results: The maximum tow-point LOD score for marker 355c18 was 6.65 at recombination fraction 0.02. The haplotype analysis narrowed down the critical region of MLC to 250 kb on chromosomal 22q tel. Conclusion: One of the causing genes of MLC was located on chromosomal 22q tel with 250 kb. Four candidate genes were considered. The heterogeneity of one informative family indicated possible existence of a second locus for MLC.

MODULATION OF THE FREQUENCY OF HUMANCYTOMEGALOViRUS-INDUCED CHROMOSOMEABERRATIONS BY CAMPTOTHECIN

The effects of selected DNA repair inhibitors on the frequency of human cytomegalovirus (HCMV)-induced chromosome aberrations in human peripheral blood lymphocytes (PBLs) were evaluated. Trealment of HCMV-infected PBLs with camptothecin (0.05 to 0.3μg/ml), an inhibitor of topoisomerase I, for 30 hr resulted in a significant (P<0.01) synergistic enhancement of the frequency of HCMV-induced chromosome damage, on the other hand, a significant increase in the frequency of chromosome damage was not noted for infected PBLs treated with either 3-aminobenzamide (3-AB) (3 to 30μg/ml), an inhibitor of poly (ADP-ribose) poiymerase, ur novobiocin 3 to 30 |ig/ml) an inhibitor of topoiso-merase I or excision repair processes for 30 hr. chromatid-type breaks including chromosome exchanges were the predominant type of chromosome aberrations observed in the HCMV-infected cells treated with camptothecin suggesting that HCMV infection is associated with the induction of single-strand DNA breaks. Furthermore, these findings suggest that HCMV infection does rol inflict dircc: DNA damage which is repaired through 3-AB- or novobiocinsensitive pathways.Human cytomegalovirus (HCMV) is a common pathogen which irferfs about 80% of the world's population causing, for the most part, persistent subcliniclil infeclions (Wellcr, 1971). A relatively small percentage of otherwise healthy immunologically competent people experience clinical HCMV disease (Cohen et al., 1985). Generalized HCMV infection, however, is the bane of individuals whose immune system is compromised (Schooley, 1990) Rubin, 1990). Molecular epidemiological studies strongly suggest that HCMV is one of the most frequent cause of congenital infections and that these infections result in a high incidence of birth defects and developmental abnormalities (Alford et al., 1990). Several studies (Nachtigal et al., 1978; Luleci et al., 1980; AbuBakar et al., 1988) have shown that HCMV infectior can result in an increase in the frequency of chromosome aberrations. Since the ability to cause chromosome damage may be significant in the induction of birth defects and possibly in HCMV-induced malignancy, we undertook the present investigation to evaluate the mechanisms by which HCMV may cause chromosome damage. In ths study, the effects of selected DNA repair inhibitors on the frequency of HCMV-induced chromosome aberrations were evaluated. The results indicae that the presence of camptothecin, but nut 3-aminobenzamidc (3-AB) ro novobiocin, results in a concentration-dependent increase in the frequent) of chromosome aberrations in HCMV-infected peripheral blood lymphocytes (PBLs). Accordingly, it is proposed that HCMV-induced chromosome damage in PBLs does not substantially involve DNA repair activities sensitive to inhibition of poly ADP-ribosylation or excision repair processes, but is related to camp of thccin-sersitive DNA repair, conceivably involving the activity of topoisomrrasc I .

ONE CASE OF LEUKEMIA INDUCED BY ^(60)Co ACCIDENT

The peripheral blood lymphocyte chromosomes in a case of 60Co γ rays accident were examined at 2.5h after exposure. The frequency of the dicentrics plus centric rings was 89% and exposure dose was estimated to be 4.78 (4.53～4.88) Gy. The examinations of lymphocyte chromosome aberration within follow-up 12α showed that the incidence of Dic+R reduced with lg regression (r = -0.9895). While the number of cells with stable aberration remained unchanged and showed a tendency to increase. During the period of leukemia, bone marrow cell chromosome aberrations were studied by method of G-banding. Of 13 cells observed, 4 cells belonged to normal karyotypes. Among 9 aberration cells, 12 aberrations were detected. The majority of which were classified as translocation, deletion and inversion. Numeric aberrations were-9,-12,-20,-22,-y. This case suggested that acute lymphocytic leukemia was induced after radiation accident.

Histone Variant H3.3:A versatile H3 variant in health and in disease

Histones are the main protein components of eukaryotic chromatin. Histone variants and histone modifications modulate chromatin structure, ensuring the precise operation of cellular processes associated with genomic DNA. H3.3, an ancient and conserved H3 variant, differs from its canonical H3 counterpart by only five amino acids, yet it plays essential and specific roles in gene transcription, DNA repair and in maintaining genome integrity. Here, we review the most recent insights into the functions of histone H3.3, and the involvement of its mutant forms in human diseases.