Gene Expression Phenotype in Autosomal Recessive Disease

描述（由申请人提供）： 常染色体隐性遗传疾病是指只有两个突变的疾病基因拷贝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，但他们通常具有与非携带者微小差异的微妙表型。大多数常染色体隐性遗传疾病是罕见的，但携带者不是。所有个体都是几种有害突变的携带者。这些突变很可能对我们之间表型的广泛变异做出重大贡献，从疾病易感性到对压力的反应变化。 在这个项目中，我们将研究辐射敏感性综合征的携带者，以了解个体对辐射反应的差异。我们将集中在四个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。体格检查和标准的生化测试不能可靠地检测出这些携带者的细微表型。我们以前的工作（Watts等，2002）确定共济失调毛细血管扩张症杂合子携带者具有“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在基线和对电离辐射的反应中也具有表达表型。具体目标是：1）鉴定基线时共济失调毛细血管扩张症、Bloom综合征、Nijmegen断裂综合征和Fanconi贫血的携带者的表达表型; 2）表征响应于电离辐射（IR）的共济失调毛细血管扩张症、Bloom综合征、Nijmegen断裂综合征和Fanconi贫血的携带者的表达表型。 这项研究的结果将对理解辐射反应变化的基础具有重要意义。该方法也可以扩展到研究隐性疾病的杂合性对人类疾病和性状的复杂遗传结构的贡献。

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.