Gene Expression Phenotype in Autosomal Recessive Disease

常染色体隐性遗传病的基因表达表型

• 批准号: 7057388
• 负责人: Vivian G Cheung
• 金额: $ 26.18万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7057388
• 关键词: Bloom syndrome; Nijmegen breakage syndrome; ataxia telangiectasia; autosomal recessive trait; cell line; clinical research; congenital aplastic anemia; gene expression; gene mutation; genetic carriers; genetic transcription; human genetic material tag; human tissue; ionizing radiation; lymphoblast; microarray technology; phenotype; radiation sensitivity

DESCRIPTION (provided by applicant): Autosomal recessive diseases are by definition those where only individuals with two mutated copies of the disease genes are affected. However, even in these diseases, there is often some manifestation in the heterozygous carriers. While there are usually no marked phenotypes in carriers, they often have subtle phenotypes that are minor differences from non-carriers. Most autosomal recessive diseases are rare but carriers are not. All individuals are carriers of several deleterious mutations. These mutations are likely to contribute significantly to the wide variation in phenotype among us, from disease susceptibility to variation in response to stress. In this project, we will study the carriers of radiosensitivity syndromes in order to understand the individual variation in response to radiation. We will focus on the gene expression profiles of heterozygous carriers of four radiosensitivity syndromes: Ataxia Telangiectasia, Nijmegen Breakage Syndrome, Bloom Syndrome and Fanconi Anemia. Physical examination and standard biochemical tests do not reliably detect the subtle phenotypes in these carriers. Our previous work (Watts et al, 2002) establishes that heterozygous carriers of Ataxia Telangiectasia have a "gene expression phenotype." In this project, we will extend and determine whether carriers of other radiosensitivity syndromes also have expression phenotypes at baseline and in response to ionizing radiation. The specific aims are: 1) Identify the expression phenotype of carriers of Ataxia Telangiectasia, Bloom Syndrome, Nijmegen Breakage Syndrome and Fanconi Anemia at baseline; 2) Characterize the expression phenotype of carriers of Ataxia Telangiectasia, Bloom Syndrome, Nijmegen Breakage Syndrome and Fanconi Anemia in response to ionizing radiation (IR). The results from this study will have important implications for understanding the basis of variation in radiation response. The approach can also be broadened to study the contribution of heterozygosity of recessive diseases to the complex genetic architecture of human diseases and traits.

描述（由申请人提供）： 根据定义，常染色体隐性遗传病是指只有具有两个突变拷贝的疾病基因的个体受到影响的疾病。然而，即使在这些疾病中，杂合子携带者也常常有一些表现。虽然携带者通常没有明显的表型，但它们通常具有与非携带者仅有微小差异的微妙表型。大多数常染色体隐性遗传疾病都很罕见，但携带者则不然。所有个体都是几种有害突变的携带者。这些突变可能对我们之间表型的广泛变化产生重大影响，从疾病易感性到对压力反应的变化。 在这个项目中，我们将研究放射敏感性综合症的携带者，以了解对放射反应的个体差异。我们将重点关注四种放射敏感性综合征杂合子携带者的基因表达谱：共济失调毛细血管扩张症、奈梅亨断裂综合征、布卢姆综合征和范可尼贫血。体格检查和标准生化测试不能可靠地检测这些携带者的细微表型。我们之前的工作（Watts 等，2002）证实共济失调毛细血管扩张症的杂合携带者具有“基因表达表型”。在这个项目中，我们将扩展并确定其他放射敏感性综合征的携带者是否也有基线和电离辐射反应的表达表型。具体目标是： 1) 鉴定共济失调性毛细血管扩张症、布卢姆综合征、奈梅亨断裂综合征和范可尼贫血携带者在基线时的表达表型； 2) 表征毛细血管扩张共济失调、布卢姆综合征、奈梅亨断裂综合征和范可尼贫血携带者对电离辐射 (IR) 的反应表达表型。 这项研究的结果对于理解辐射响应变化的基础具有重要意义。该方法还可以扩展到研究隐性疾病杂合性对人类疾病和性状的复杂遗传结构的贡献。