The Genetic Basis of the GAPO Progeroid Syndrome

GAPO 早衰综合症的遗传基础

• 批准号: 8445221
• 负责人: Calum A. MacRae
• 金额: $ 21.09万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445221
• 关键词: Affect; Aging; Aging-Related Process; Alopecia; Amenorrhea; Area; Atherosclerosis; Atrophic; Atrophic condition of skin; Biology; Cell Line; Chromosome Mapping; Chromosomes; Clinical; Collaborations; Cytogenetics; DNA Repair Enzymes; Data; Defect; Development; Disease; Evaluation; Failure; Family; Fatty acid glycerol esters; Genes; Genetic; Genomics; Genotype; Growth; Hair; Hereditary Disease; Human; Human Genetics; In Vitro; Individual; Infection; Inherited; Knock-in Mouse; Light; Location; Longevity; Maps; Modeling; Molecular; Molecular Genetics; Mutagenesis; Mutation; Nuclear; Oligospermia; Optic Atrophy; Osteopenia; Osteoporosis; Pathway interactions; Patients; Phenotype; Premature Menopause; Premature aging syndrome; Proteins; Rare Diseases; Resources; Skin; Syndrome; Technology; Testing; Therapeutic; Tooth eruption; Translating; Variant; Vascular Diseases; Work; Zebrafish; Zinc Fingers; appendage; autosomal recessive trait; base; design; disease-causing mutation; gene function; in vivo Model; insight; kindred; male; next generation sequencing; novel; nuclease; positional cloning; racial and ethnic; recessive genetic trait; research study; subcutaneous; trait

DESCRIPTION (provided by applicant): Mendelian forms of human genetic disease can be viewed as natural mutagenesis experiments. Over the past decade many disease-causing mutations have been identified through positional cloning: the identification of the causal gene purely on the basis of its genetic location. One unique form of aging, that to date has not been studied at the molecular level, is the Growth retardation, Alopecia, Pseudoanodontia, and Optic atrophy (or GAPO) syndrome. Through extensive clinical efforts and worldwide collaborations we have collected 17 individuals affected with the GAPO progeroid syndrome and identified a genetic locus on Chromosome 2p. We now propose to refine the genetic locus and clone the causal gene or genes as outlined in the following Specific Aims; Aim 1-Refined mapping of the GAPO genetic locus Under the assumption that the GAPO syndrome is a monogenic recessive trait (well supported by all of the available data) we will use homozygosity mapping with lllumina BeadArray technology (the Infinium HumanHap 610K SNP panel) to identify the minimal genetic locus responsible for the syndrome. Aim 2- Identification of the GAPO syndrome gene Using modern approaches to positional cloning, including next generation sequencing, we will screen genes within the final genetic interval for mutations in GAPO syndrome patients. Candidates will be tested in other GAPO patients, in vitro using cell lines from GAPO subjects, and through systematic antisense morpholino knockdown in the zebrafish model. The coexistence of several developmental phenotypes in GAPO syndrome will allow this latter effort. The work we have outlined is designed to identify the causal gene in this unique progeroid syndrome, and will immediately enable the development of in vivo models using mouse knock-in of specific human mutations. The pathways identified will be explored in other forms of human aging, as well as in common disease entities shared with the GAPO syndrome including atherosclerosis, osteoporosis and osteopenia and gonadal failure.

描述（由申请人提供）： 孟德尔人的人类遗传疾病形式可以看作是自然诱变实验。在过去的十年中，通过位置克隆确定了许多引起疾病的突变：纯粹基于其遗传位置的因果基因的鉴定。迄今为止尚未在分子水平上研究的一种独特的衰老形式是生长迟缓，脱发，假阳极牙和视神经萎缩症（或GAPO）综合征。通过广泛的临床努力和全球合作，我们收集了17名患有Gapo后代综合征的人，并确定了2p染色体上的遗传基因座。现在，我们建议完善遗传基因座并克隆因果基因或基因，如以下特定目的所述；在Gapo遗传基因座的AIM 1映射是在假设Gapo综合征是一种单基因隐性性状（在所有可用数据的情况下得到很好的支持），我们将使用Lllumina Beadarray Technology（Infinium Humanhap 610k SNP SNP面板）来确定对微型遗传学的纯合型绘图。 AIM 2-使用现代的位置克隆方法鉴定GAPO综合征基因，包括下一代测序，我们将在GAPO综合征患者突变的最终遗传间隔内筛选基因。候选人将在其他GAPO患者中进行测试，使用GAPO受试者的细胞系在体外以及斑马鱼模型中通过系统的反义型型敲低测试。 GAPO综合征中几种发展表型的共存将允许后一种努力。我们概述的工作旨在识别这种独特的后代综合征中的因果基因，并将立即使用特定人类突变的小鼠敲入来开发体内模型。确定的途径将以其他形式的人类衰老以及与GAPO综合征共享的共同疾病实体进行探索，包括动脉粥样硬化，骨质疏松症和骨质骨质减少和性腺衰竭。

项目成果

Action and the actionability in exome variation.

外显子组变异的作用和可操作性。

• DOI: 10.1161/circgenetics.112.965152
• 发表时间: 2012
• 期刊: Circulation. Cardiovascular genetics
• 作者: MacRae,CalumA