Somatic Mosaicism in the Wiskott-Aldrich Syndrome

威斯科特-奥尔德里奇综合征中的体细胞镶嵌

• 批准号: 7864037
• 负责人: Brian R. Davis
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-10 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7864037
• 关键词: Amino Acid Sequence; B-Lymphocytes; Biology; Cells; DNA Sequence; Data; Development; Disease; Epidermolysis Bullosa; Event; Exons; Fanconi' s Anemia; Frequencies; Genotype; Germ Lines; Goals; Hereditary Disease; Immunologic Deficiency Syndromes; Inherited; Introns; Life; Modeling; Mosaicism; Mutation; Patients; Pilot Projects; Proteins; Site; Somatic Cell; Somatic Mutation; T memory cell; T-Lymphocyte; Tyrosinemias; Wiskott-Aldrich Syndrome; X-Linked Severe Combined Immunodeficiency; base; fitness; in vivo; monocyte; novel; progenitor; protein function; public health relevance; restoration

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.

描述（由申请人提供）：体细胞嵌合现象已在几种遗传性疾病中描述，包括原发性免疫缺陷病（例如Wiskott-Aldrich综合征[WAS]、X连锁严重联合免疫缺陷）、范可尼贫血、大疱性表皮病和酪氨酸血症。虽然体细胞嵌合现象（由原始野生型序列的回复或第二位点回复突变引起）在WAS患者中观察到的频率很高，并且显然是疾病的一个重要方面，但我们对这种现象的理解目前非常有限。我们最近在WAS患者中发现了前所未有的回复突变基因型多样性，这挑战了目前认为自发回复突变是罕见事件且其发生仅限于长寿祖细胞的观点。相反，我们的数据与自发WAS突变在体细胞中以一定频率起源的模型一致;然后通过体内选择对这些细胞起作用，富集具有部分或完全恢复WAS蛋白（WASp）功能的细胞。我们提出了一个新的视角，在其中查看体细胞嵌合体-在一个生殖系WAS突变附近的体细胞突变谱基本上探讨了可能的WASp氨基酸序列的景观，最终有利于那些有足够的健身在体内选择。在这项初步研究中，我们建议首先全面检查WAS患者回复突变基因型探索的WAS DNA序列空间。其次，我们将研究这些回复突变基因型探索的WASp适应性景观，重点是WASp在T淋巴细胞中的几个关键功能。我们建议，从进化生物学的角度来看，WAS体细胞镶嵌提供了一个概念框架，了解回复突变WAS突变的起源和在体内选择这些突变的细胞。公共卫生相关性：这项探索性研究旨在确定遗传性遗传病患者（特别是Wiskott-Aldrich综合征）体细胞嵌合体发展中的关键事件。