Clinical and Basic Investigations into Known and Suspected

对已知和疑似病例的临床和基础调查

基本信息

批准号：
9127287
负责人：
William Allen Gahl
金额：
$ 12万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-29 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9127287
关键词：
Affect Anemia Biological Markers Cardiac Clinical Congenital Disorders Consultations DNA DNA Sequence DNA Sequence Alteration Defect Dermatologic Development Diagnosis Diagnostic Disease Disease Progression Dolichol Endocrine Etiology Exhibits Frequencies Genes Glycosaminoglycans Glycosylphosphatidylinositols Golgi Apparatus Ichthyoses Immunologics Inborn Genetic Diseases Investigation Laboratories Lipids Lung Mass Spectrum Analysis Medical Genetics Metabolism Molecular Monitor Musculoskeletal Mutation Mutation Analysis Natural History Nature Neurologic Neurologic Symptoms Pathway interactions Patients Pattern Phase Physical Examination Physicians Plasma Polysaccharides Protein Glycosylation Proteins Rare Diseases Recording of previous events Research Serum Severity of illness Sterols Symptoms Systemic disease Time Tissues Transferrin base diagnostic screening disease natural history effective therapy exome sequencing gastrointestinal glycosylation insight isoprenoid medical specialties mevalonate outcome forecast research clinical testing

项目摘要

Dolichols are long-chain isoprenoid products of the mevalonate pathway that act in the initial steps of glycosylation of proteins and certain lipids. Recently, inherited disorders of dolichol synthesis or utilization have been discovered. Patients present with variable multiorgan symptoms and exhibit defective lipid and protein glycosylation. Few patients have been identified and little or nothing is known about the longitudinal natural history these diseases. Although many patients have underglycosylated proteins, a biomarker that correlates with disease severity or can be used for monitoring disease progression has not been identified. Further, effective therapy for the isoprenoid diseases does not yet exist. Based on the known dolichol synthesis pathway, it is likely that new diseases of dolichol metabolism are waiting to be identified. We propose to define the natural history of inborn errors of dolichol metabolism by systematically characterizing their clinical features and documenting how they change over time. Comprehensive clinical evaluations will be performed every year to determine the frequency and variability of symptoms. We will search for the most useful biomarkers that correlate with disease severity and progression. For those patients lacking a DNA diagnosis, we will perform mutation analysis to characterize the molecular defects in the known dolichol genes and search for additional new dolichol-related disease genes using whole exome sequencing. In this fashion, we will achieve new insight into the clinical features and natural history of these rare diseases.

多利匹醇是甲谷酸酯途径的长链类异丙素产物，在蛋白质和某些脂质的糖基化初始步骤中起作用。最近，已经发现了多利希尔合成或利用的遗传疾病。患者出现了可变的多机器人症状，并且表现出缺陷的脂质和蛋白质糖基化。很少有患者被鉴定出来，对这些疾病的纵向自然病史几乎一无所知。尽管许多患者患有糖基化蛋白质，但尚未确定与疾病严重程度或可用于监测疾病进展的生物标志物。此外，尚不存在针对类异丙疾病的有效疗法。基于已知的Dolichol合成途径，可能正在等待识别多利希尔代谢的新疾病。我们建议通过系统地表征其临床特征并记录它们如何随着时间的变化来定义多利琴代谢的天生自然历史。每年将进行全面的临床评估，以确定症状的频率和变异性。我们将寻找与疾病严重程度和进展相关的最有用的生物标志物。对于那些缺乏DNA诊断的患者，我们将进行突变分析，以表征已知的Dolichol基因中的分子缺陷，并使用整个外显子组测序搜索其他新的Dolichol相关疾病基因。以这种方式，我们将对这些罕见疾病的临床特征和自然史获得新的见解。