胞质分裂阻滞微核法对AT细胞高辐射敏感性的研究

目的 研究源于毛细血管扩张性共济失调症(ataxia-telangiectasia,AT)患者皮肤的成纤维细胞系AT5BIVA(AT细胞)的辐射敏感性.方法本实验以源于正常人皮肤的成纤维细胞系GM0639(GM细胞)为对照,采用胞质分裂阻滞微核法(Cytokinesis-Block micronucleus method),在AT细胞和GM细胞经60Co γ射线0、1、2、3、4 Gy照射后,观察比较AT细胞和GM细胞之间微核率及微核细胞率的差异,并分别进行曲线拟合.结果在1、2、3、4 Gy剂量照射下,AT细胞微核率及微核细胞率均明显高于GM细胞,其差异有非常显著性 (P＜0.01),并且两者微核率及微核细胞率均与剂量呈正相关,均可拟合成剂量效应直线方程y=a bx,微核率及微核细胞率直线回归方程斜率AT细胞明显大于GM细胞(P＜0.01).结论辐射敏感性AT细胞显著高于GM细胞,AT患者AT细胞具有高辐射敏感性.     

The relationship between nutritional status,vitamin A and zinc levels and oxidative stress in patients with ataxia-telangiectasia

BackgroundAtaxia-telangiectasia (A-T) is a rare and degenerative disease that leads to varying degrees of immunodeficiency, oxidative stress, and malnutrition. Vitamin A and zinc are essential for immune function and antioxidant defence.ObjectiveTo compare levels of retinol, beta carotene, and zinc in patients with ataxia-telangiectasia and healthy controls.MethodsWe performed a cross-sectional study with 14 AT patients and 14 healthy controls matched for age and gender. All participants underwent a nutritional and laboratory evaluation comprising concentrations of retinol, beta carotene, serum and erythrocyte zinc, malondialdehyde (MDA), T lymphocyte numbers (CD4⁺ and CD8⁺) and immunoglobulin (IgA).ResultsThe AT patients showed high rates of malnutrition with reduced lean body mass when compared to the control group. However, the concentrations of MDA, retinol, beta carotene, and serum and erythrocyte zinc in AT patients were similar to those of the control group. The retinol levels presented a negative correlation with MDA and positive correlation with IgA serum level.ConclusionsThe AT patients assessed showed no change in nutritional status for vitamin A and zinc; however, they presented severe impairment in overall nutritional status observed and correlation between retinol with MDA and IgA.     

DISSEMINATED HERPES SIMPLEX VIRUS INFECTION IN ATAXIA-TELANGIECTASIA

ABSTRACT. The clinical and pathological features are described in a child with ataxia-telangiectasia, complicated by fatal disseminated herpes simplex virus infection. Herpes simplex virus was isolated from the patient's blood, and the histopathological findings in the skin, liver and adrenals were consistent with herpes simplex virus infection. The patient had a combined immune deficiency state, as a part of the ataxia-telangiectasia syndrome. She had impaired cellular immune response to herpes simplex virus and developed no antibodies against the virus. To our knowledge, this is the first fatal case of disseminated herpes simplex virus infection in ātaxia-telangiectasia.     

Workshop Report: European Workshop on Ataxia-Telangiectasia,Frankfurt, 2011

Abstract: Ataxia-telangiectasia (A-T) is a devastating human recessive disorder characterized by progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and cancer susceptibility. The European Workshop on Ataxia-Telangiectasia 2011 in Frankfurt focused on status quo of patient care and future clinical research directions. In Europe, approximately 600 patients are registered and many national websites have been established. During the meeting, guidelines of patient care were discussed and all participants agreed to build up an European A-T research network in near future to bring basic research and new therapies into clinical applications.     

Claves para afrontar el reto diagnóstico de las heredoataxias recesivas

Introduction

Autosomal recessive spinocerebellar ataxia refers to a large group of diseases affecting the cerebellum and/or its connections, although they may also involve other regions of the nervous system. These diseases are accompanied by a wide range of systemic manifestations (cardiopathies, endocrinopathies, skeletal deformities, and skin abnormalities).

Sequence analysis of the ATM gene in 20 patients with RTOG grade 3 or 4 acute and/or late tissue radiation side effects

Purpose: Patients with ataxia-telangiectasia (A-T) show greatly increased radiation sensitivity and cancer predisposition. Family studies imply that the otherwise clinically silent heterozygotes of this autosomal recessive disease run a 3.5 to 3.8 higher risk of developing cancer. In vitro studies suggest moderately increased cellular radiation sensitivity of A-T carriers. They may also show elevated clinical radiosensitivity. We retrospectively examined patients who presented with severe adverse reactions during or after standard radiation treatment for mutations in the gene responsible for A-T, ATM, considering a potential means of future identification of radiosensitive individuals prospectively to adjust dosage schedules.

Material and Methods: We selected 20 cancer patients (breast, 11; rectum, 2; ENT, 2; bladder, 1; prostate, 1; anus, 1; astrocytoma, 1; Hodgkins lymphoma, 1) with Grade 3 to 4 (RTOG) acute and/or late tissue radiation side effects by reaction severity. DNA from the peripheral blood of patients was isolated. All 66 exons and adjacent intron regions of the ATM gene were PCR-amplified and examined for mutations by a combination of agarose gel electrophoresis, single-stranded conformational polymorphism (SSCP) analysis, and exon-scanning direct sequencing.

Results: Only 2 of the patients revealed altogether four heteroallelic sequence variants. The latter included two single-base deletions in different introns, a single-base change causing an amino acid substitution in an exon, and a large insertion in another intron. Both the single-base deletions and the single-base change represent known polymorphisms. The large insertion was an Alu repeat, shown not to give rise to altered gene product.

Conclusions: Despite high technical efforts, no unequivocal ATM mutation was detected. Nevertheless, extension of similar studies to larger and differently composed cohorts of patients suffering severe adverse effects of radiotherapy, and application of new technologies for mutation detection may be worthwhile to assess the definite prevalence of significant ATM mutations within the group of radiotherapy patients with adverse reactions. To date, it must be recognized that our present results do not suggest that heterozygous ATM mutations are involved in clinically observed radiosensitivity but, rather, invoke different genetic predisposition or so far unknown exogenous factors.     

ATM mutation spectrum in Russian children with ataxia-telangiectasia

Ataxia-telangiectasia (AT) is a severe autosomal recessive orphan disease characterized by a number of peculiar clinical manifestations. Genetic diagnosis of AT is complicated due to a large size of the causative gene, ATM.We used next-generation sequencing (NGS) technology for the ATM analysis in 17 children with the clinical diagnosis of AT.Biallelic mutations in the ATM gene were identified in all studied subjects; these lesions included one large gene rearrangement, which was reliably detected by NGS and validated by multiplex ligation-dependent probe amplification (MLPA). There was a pronounced founder effect, as 17 of 30 (57%) pathogenic ATM alleles in the patients of Slavic origin were represented by three recurrent mutations (c.5932G > T, c.450_453delTTCT, and c.1564_1565delGA).These data have to be taken into account while considering the genetic diagnosis and screening for ataxia-telangiectasia syndrome.     

A practice-based survey of familial age-related maculopathy

PURPOSE : We evaluated the efficacy of a practice-based survey of age-related maculopathy (ARM) to identify potential families for molecular genetic studies. Demographic and ophthalmic features of the eligible study population were compared with responders and with individuals who reported a positive family history of ARM. METHODS : Individuals seen within a three-year period in a comprehensive ophthalmic practice were identified through billing codes. Clinical records were reviewed, coded, and merged with questionnaire responses. Patient identifiers were removed prior to analyses. RESULTS : There were no significant differences between the respondents and the eligible cohort with respect to gender, age, or type of macular degeneration. Comparable percentages of younger and older individuals with ARM reported positive family histories. The distribution of atrophic macular degeneration, choroidal neovascular membranes, and milder forms of the disease among the individuals reporting positive family histories corresponded to the distribution of the entire eligible cohort of patients. CONCLUSIONS : This recruitment strategy for ARM families is cost-effective and confirmed a high prevalence of familial ARM. The respondents are representative of the general ARM population. This approach is applicable for other ophthalmic genetic conditions.     

Functional polymorphism rs189037 in the promoter region of ATM gene is associated with angiographically characterized coronary stenosis

Objectives

To evaluate the association between the single nucleotide polymorphism rs189037 of the ataxia-telangiectasia mutated (ATM) gene and angiographically characterized coronary stenosis as well as the molecular basis of this association.

Results

In 562 patients treated at the Department of Cardiology, West China Hospital, a significant association was found between polymorphism rs189037 and angiographically characterized coronary stenosis. For the T versus C allele, the adjusted OR was 0.79 (95%CI 0.67–0.92, P = 0.003), using the allele frequency model; for TT versus CT/CC, the adjusted OR was 0.36 (95%CI 0.21–0.59, P = 0.00006), using the recessive model; and for TT/CT versus CC, the adjusted OR was 0.54 (95%CI 0.29–1.02, P = 0.06), using the dominant model. An antagonism was found between polymorphism rs189037 and diabetes mellitus (P = 0.003). In coronary artery disease (CAD) patients, the TT genotype of rs189037 was associated with higher ATM mRNA expression (F = 4.23, P = 0.02) in peripheral mononuclear cells than the CC or CT genotypes.

Conclusion

Polymorphism rs189037 may influence the expression of ATM mRNA in CAD patients. It is also associated with the degree of coronary stenosis. Moderately low expression of the ATM gene may be associated with the development of coronary atherosclerosis.