Mutational Analysis of Peroxisome Biogenesis Disorders

过氧化物酶体生物发生障碍的突变分析

基本信息

  • 批准号:
    6953829
  • 负责人:
  • 金额:
    $ 22.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2005
  • 资助国家:
    美国
  • 起止时间:
    2005-08-03 至 2007-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Peroxisome biogenesis disorders (PBDs) are inborn errors of metabolism with considerable clinical, biochemical, and genetic heterogeneity. The rational design of effective treatments for these disorders requires the precise identification of the causative molecular defects in each PBD patient. However, the diagnosis of PBD patients is time consuming, labor intensive, and highly specialized since it requires establishing fibroblast cultures and performing biochemical lipid analyses for every individual tested. Our goal is to rapidly and efficiently determine the genetic basis for PBDs in order to improve the likelihood of identifying and developing therapies that are most effective for each patient. We hypothesize that high-throughput mutation detection and gene expression assays can rapidly and efficiently diagnose the molecular basis for PBDs. To test our hypothesis, we will identify causative mutations in genomic DNA from patients within the Zellweger syndrome-neonatal adrenoleukodystrophy-infantile Refsum disease (ZS-NALDIRD) spectrum of PBDs and analyze their activity in cultured fibroblasts from patients with known mutations. In this proposal, we will develop novel oligonucleotide microarray-based diagnostics to rapidly and efficiently screen genomic DNA from patient blood samples for mutations in five genes (PEX1, PEX6, PEX10, PEX12, and PEX26) which account for over 90% of ZS-NALD-IRD cases (Specific Aim 1). We will determine the specificity and sensitivity of these assays by blinded mutational analyses of ZS-NALD-IRD patients with known mutations in these genes. After this validation step, we will use these microarray assays to uncover the genetic defects responsible for clinical phenotypes in one hundred ZS-NALD-IRD patients. Furthermore, we will conduct functional assays to determine the functional significance of missense mutations in order to better correlate patient genotype with clinical phenotypes (Specific Aim 2). First, we will prioritize missense changes for analysis based on the conservation of these amino acids in other species and allele frequencies in the general population. Afterwards, we will construct lentiviral vectors that can transduce wild type and mutated PEX genes into PEX1, PEX6, PEX10, PEX12, and PEX26 null cell lines that lack functional peroxisomes due to defects in peroxisome assembly. We will determine the functional activity of PEX genes containing missense changes relative to their wild type counterparts by screening for the appearance of peroxisomes in the appropriately transduced null cell lines. Overall, these mutation detection (Specific Aim 1) and functional (Specific Aim 2) assays will provide valuable resources for the precise molecular diagnosis and characterization of patients within the ZS-NALD-IRD spectrum. In addition to providing the genetic information needed for the rational design of therapies, these high-throughput genetic tests will allow for more accurate predictions of clinical outcomes for these individuals and facilitate prenatal diagnosis in future pregnancies.
描述(由申请方提供):过氧化物酶体生物合成障碍(PBD)是一种先天性代谢缺陷,具有相当大的临床、生化和遗传异质性。这些疾病的有效治疗的合理设计需要精确鉴定每个PBD患者的致病分子缺陷。然而,PBD患者的诊断是耗时的,劳动密集型的,并且高度专业化,因为它需要建立成纤维细胞培养物并对每个测试个体进行生化脂质分析。我们的目标是快速有效地确定PBD的遗传基础,以提高识别和开发对每个患者最有效的治疗方法的可能性。我们假设高通量突变检测和基因表达分析可以快速有效地诊断PBD的分子基础。为了验证我们的假设,我们将确定Zellweger综合征-新生儿肾上腺脑白质营养不良-婴儿Refsum病(NALDIRD)PBD谱内患者的基因组DNA中的致病突变,并分析其在已知突变患者的培养成纤维细胞中的活性。在这项提案中,我们将开发新的基于寡核苷酸微阵列的诊断方法,以快速有效地从患者血液样本中筛选基因组DNA中的五个基因(PEX 1,PEX 6,PEX 10,PEX 12和PEX 26)突变,这些基因占90%以上的EST-NALD-IRD病例(具体目标1)。我们将通过对这些基因中具有已知突变的EST-NALD-IRD患者进行盲法突变分析来确定这些检测的特异性和灵敏度。在这个验证步骤之后,我们将使用这些微阵列检测来揭示100名ERAD-NALD-IRD患者中导致临床表型的遗传缺陷。此外,我们将进行功能测定,以确定错义突变的功能意义,以便更好地将患者基因型与临床表型相关联(具体目标2)。首先,我们将根据这些氨基酸在其他物种中的保守性和一般人群中的等位基因频率,优先考虑错义变化进行分析。然后,我们将构建慢病毒载体,可以将野生型和突变的PEX基因导入由于过氧化物酶体组装缺陷而缺乏功能性过氧化物酶体的PEX 1,PEX 6,PEX 10,PEX 12和PEX 26空细胞系中。我们将通过筛选适当转导的空细胞系中过氧化物酶体的出现来确定相对于野生型对应物含有错义变化的PEX基因的功能活性。总体而言,这些突变检测(特异性目的1)和功能(特异性目的2)检测将为精确的分子诊断和表征EST-NALD-IRD谱内的患者提供有价值的资源。除了提供合理设计治疗所需的遗传信息外,这些高通量基因检测还可以更准确地预测这些个体的临床结果,并促进未来妊娠的产前诊断。

项目成果

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JOSEPH G HACIA其他文献

JOSEPH G HACIA的其他文献

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{{ truncateString('JOSEPH G HACIA', 18)}}的其他基金

Development of Targeted Therapies for Peroxisome Biogenesis Disorders: Current and future prospects
过氧化物酶体生物合成障碍靶向治疗的发展:当前和未来前景
  • 批准号:
    9261342
  • 财政年份:
    2016
  • 资助金额:
    $ 22.01万
  • 项目类别:
Development of Targeted Therapies for Peroxisome Biogenesis Disorders: Current and future prospects
过氧化物酶体生物合成障碍靶向治疗的发展:当前和未来前景
  • 批准号:
    9447324
  • 财政年份:
    2016
  • 资助金额:
    $ 22.01万
  • 项目类别:
Development of Targeted Therapies for Peroxisome Biogenesis Disorders: Current and future prospects
过氧化物酶体生物合成障碍靶向治疗的发展:当前和未来前景
  • 批准号:
    9440507
  • 财政年份:
    2016
  • 资助金额:
    $ 22.01万
  • 项目类别:
COMPARATIVE GENOMICS OF PEROXISOMAL LIPID METABOLISM
过氧化物酶体脂质代谢的比较基因组学
  • 批准号:
    8171359
  • 财政年份:
    2010
  • 资助金额:
    $ 22.01万
  • 项目类别:
Comparative Genomics of Peroxisomal Lipid Metabolism
过氧化物酶体脂质代谢的比较基因组学
  • 批准号:
    7931167
  • 财政年份:
    2009
  • 资助金额:
    $ 22.01万
  • 项目类别:
COMPARATIVE GENOMICS OF PEROXISOMAL LIPID METABOLISM
过氧化物酶体脂质代谢的比较基因组学
  • 批准号:
    7723631
  • 财政年份:
    2008
  • 资助金额:
    $ 22.01万
  • 项目类别:
Comparative Genomics of Peroxisomal Lipid Metabolism
过氧化物酶体脂质代谢的比较基因组学
  • 批准号:
    7392358
  • 财政年份:
    2005
  • 资助金额:
    $ 22.01万
  • 项目类别:
Mutational Analysis of Peroxisome Biogenesis Disorders
过氧化物酶体生物发生障碍的突变分析
  • 批准号:
    7140209
  • 财政年份:
    2005
  • 资助金额:
    $ 22.01万
  • 项目类别:
Comparative Genomics of Peroxisomal Lipid Metabolism
过氧化物酶体脂质代谢的比较基因组学
  • 批准号:
    7217534
  • 财政年份:
    2005
  • 资助金额:
    $ 22.01万
  • 项目类别:
Comparative Genomics of Peroxisomal Lipid Metabolism
过氧化物酶体脂质代谢的比较基因组学
  • 批准号:
    6920952
  • 财政年份:
    2005
  • 资助金额:
    $ 22.01万
  • 项目类别:

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