Gene Expression Phenotype in Autosomal Recessive Disease

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疾病基因突变副本的个体才会受到影响。然而，即使在这些疾病中，杂合子携带者也往往会有一些表现。虽然携带者通常没有明显的表型，但他们经常有与非携带者略有不同的微妙表型。大多数常染色体隐性遗传病是罕见的，但携带者并不罕见。所有个体都是几种有害突变的携带者。这些突变很可能导致我们在表型上的广泛差异，从疾病易感性到对应激反应的变化。 在本项目中，我们将研究放射敏感性综合征的携带者，以了解个体对辐射的反应差异。我们将重点研究四种放射敏感性综合征的杂合子携带者的基因表达谱：共济失调毛细血管扩张症、奈梅根破裂综合征、布卢姆综合征和范可尼贫血。体检和标准生化测试不能可靠地检测出这些携带者的细微表型。我们之前的工作(Watts等人，2002)确定了毛细血管扩张性共济失调的杂合子携带者具有“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有表达表型。其具体目的是：1)确定毛细血管扩张共济失调、Bloom综合征、Nijmegen破裂综合征和Fanconi贫血携带者在基线水平的表达表型；2)表征毛细血管扩张共济失调、Bloom综合征、Nijmegen破裂综合征和Fanconi贫血携带者对电离辐射(IR)的反应。 这项研究的结果将对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.