Analyse der variablen Expressivität beim Nijmegen Breakage Syndrom (NBS)

奈梅亨断裂综合征（NBS）的变量表达分析

• 批准号: 129836450
• 负责人: Professor Dr. Martin J. Digweed
• 金额: --
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/129836450?language=en
• 关键词: Analyse; der; variablen; Expressivit; beim

Over 90% of patients with Nijmegen Breakage Syndrome (NBS), a hereditary cancer disorder, are homoallelic for a 5bp deletion in the NBN gene. This hypomorphic mutation leads to a carboxyterminal protein fragment. Haploinsufficiency for NBN is associated with increased cancer risk for heterozygotes, and variation in the amount of the carboxyterminal protein correlates in homozygotes with cancer occurrence. Discovering the molecular basis for this variation is a major goal of the project and for this, patient cells and a humanized mouse model will be employed. Further examples of variable expressivity in NBS are found at the level of immunodeficiency and chromosomal instability, reflecting NBN’s role in DNA double strand break repair. Potential modifiers of NBN will be searched for by defining the proteins interacting directly with NBN or affected by its absence. These modifiers will then be evaluated in our patient panel for their contribution to phenotypic variability.

超过90％的Nijmegen Breakage综合征患者（NBS）是一种遗传性癌症，是NBN基因中5BP缺失的同型。这种型型突变导致羧基末期蛋白质片段。 NBN的单倍不足与杂合子的癌症风险增加有关，羧基蛋白与癌症发生的羧基末期蛋白量的变化有关。发现这种变化的分子基础是该项目的主要目标，为此，将雇用患者细胞和人源化的小鼠模型。在免疫缺陷和染色体不稳定性水平上发现了NBS中可变表达性的进一步示例，这反映了NBN在DNA双链断裂修复中的作用。通过直接定义与NBN相互作用或受其缺失影响的蛋白质，将搜索NBN的潜在修饰符。然后，这些修饰符将在我们的患者面板中评估，以便它们对表型变异性的贡献。

项目成果

Nijmegen breakage syndrome: the clearance pathway for mutant nibrin protein is allele specific.

奈梅亨断裂综合征：突变尼布蛋白的清除途径是等位基因特异性的

• DOI: 10.1016/j.gene.2013.02.033
• 发表时间: 2013
• 期刊: Gene
• 影响因子: 3.5
• 作者: Salewsky B;Wessendorf P;Hirsch D;Krenzlin H;Digweed M
• 通讯作者: Digweed M

DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress

• DOI: 10.1371/journal.pgen.1002557
• 发表时间: 2012-03-01
• 期刊: PLOS GENETICS
• 影响因子: 4.5
• 作者: Krenzlin, Harald;Demuth, Ilja;Digweed, Martin
• 通讯作者: Digweed, Martin