Somatic Mosaicism in the Wiskott-Aldrich Syndrome

描述(申请人提供)：体细胞嵌合体已在几种遗传性疾病中被描述，包括原发免疫缺陷疾病(例如，Wiskott-Aldrich综合征、X连锁严重联合免疫缺陷)、Fanconi贫血、大疱性表皮松解症和酪氨酸血症。尽管体细胞嵌合体(由回复到原始野生型序列或由第二位点突变引起)在较高频率的WAS患者中观察到，并且显然是疾病的一个重要方面，但我们目前对这一现象的了解严重受限。我们最近在一名AS患者中发现了前所未有的回复基因型多样性，挑战了目前的观念，即自发回复是罕见的事件，而且它们的出现仅限于长寿的祖细胞。相反，我们的数据与一个模型是一致的，在该模型中，自发的was突变在体细胞中以一定的频率起源；然后通过体内选择作用于这些细胞，丰富那些具有部分或完全恢复was蛋白(WASP)功能的细胞。我们提出了一种新的视角来看待体细胞嵌合体-其中胚系附近的体细胞突变谱是突变-本质上探索了可能的黄蜂氨基酸序列的格局，最终有利于那些具有足够适合性的体内选择。在这项先导性研究中，我们建议首先全面检查这名AS患者的回复基因所探索的WASDNA序列空间。其次，我们将考察这些突变基因所探索的黄蜂适合性格局，重点关注黄蜂在T淋巴细胞中的几个关键功能。我们认为，从进化生物学的角度来看是体细胞嵌合体，为理解回复突变的起源和体内携带这些突变的细胞的选择提供了一个概念性框架。公共卫生相关性：这项探索性研究试图确定遗传性疾病患者，特别是Wiskott-Aldrich综合征患者体细胞嵌合体发展过程中的关键事件。

DESCRIPTION (provided by applicant): Somatic mosaicism has been described in several genetic diseases including Primary Immunodeficiency Diseases (e.g. Wiskott-Aldrich Syndrome [WAS], X-linked Severe Combined Immunodeficiency), Fanconi Anemia, Epidermolysis Bullosa, and Tyrosinemia. Although somatic mosaicism (resulting either from a reversion to the original wild-type sequence or from a second-site revertant mutation) is observed in a high frequency of patients with WAS and is clearly an important aspect of disease, our understanding of this phenomenon is presently severely limited. Our recent identification of an unprecedented diversity of revertant genotypes in a WAS patient challenges the current notion that spontaneous reversions are rare events and that their occurrence is restricted to long-lived progenitors. Rather, our data are consistent with a model in which spontaneous WAS mutations originate with some frequency in somatic cells; these cells are then are acted upon by in vivo selection enriching those with partial or full restoration of WAS protein (WASp) function. We propose a novel perspective in which to view somatic mosaicism - in which the spectrum of somatic mutations in the vicinity of a germ-line WAS mutation essentially explores the landscape of possible WASp amino acid sequences, ultimately favoring those with sufficient fitness for in vivo selection. In this pilot study, we propose to first comprehensively examine the WAS DNA sequence space explored by revertant genotypes in this WAS patient. Second, we will examine the WASp fitness landscape explored by these revertant genotypes, focusing on several critical functions of WASp in T-lymphocytes. We propose that viewing WAS somatic mosaicism from an evolutionary biology perspective offers a conceptual framework for understanding the origination of revertant WAS mutations and the in vivo selection of cells bearing these mutations. Public Health Relevance: This exploratory study seeks to identify critical events in the development of somatic mosaicism in patients with inherited genetic disease - in particular, the Wiskott-Aldrich Syndrome.