TRANSTHYRETIN IN FAMILIAL AMYLOIDOTIC POLYNEUROPHATHY

家族性淀粉样多发性神经病中的甲状腺素运载蛋白

• 批准号: 3160781
• 负责人: MARTHA M SKINNER
• 金额: $ 16.9万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-01 至 1995-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3160781
• 关键词: amyloid proteins; amyloidosis; antibody formation; autosomal dominant trait; biopsy; circular dichroism; diagnosis design /evaluation; elastases; endopeptidases; enzyme linked immunosorbent assay; enzyme mechanism; gene mutation; genotype; hereditary peripheral nervous system disorder; human subject; immunocytochemistry; monoclonal antibody; mutant; neutrophil; nucleic acid probes; oligonucleotides; protein biosynthesis; proteolysis; serine

DESCRIPTION: (Adapted from the applicant's abstract) The hereditary form of amyloidosis, familial amyloidotic polyneuropathy (FAP) is an autosomal dominantly inherited condition associated with a mutant form of the protein transthyretin (TTR, also called pre-albumin). It is a rare late-onset genetic disease which results in rapid deterioration due to peripheral and autonomic neuropathy and cardiomyopathy in the third or fourth decade of life. It raises the question of how an abnormal gene which is present from birth produces disease a decade later. Biopsies have proven that amyloid deposition begins just prior to the time of first symptoms. Six variant forms of the amyloid precursor TTR had been identified. Each involves a single amino acid substitution in the normal 127 amino acid chain of TTR. In their population of patients from 28 families with FAP, the applicants have recently identified one new variant and have other families with variants of unknown type. They differ phenotypically and in ethnic origin from each other and do not have one of the known TTR variants. The applicants proposed to examine their DNA and/or plasma for TTR variations that have resulted in amyloid deposition and to determine techniques for the genetic testing of that mutation. One patient with a homozygous mutant pattern will provide the unique opportunity to examine its proteolysis and to develop an antibody only to the mutant protein. They plan to test the hypothesis that variations in clinical symptoms, age at onset, and disease progression may be explained by factors other than the single nucleotide mutation in the TTR gene. Their preliminary data suggest a radical change in the beta formation of the mutant TTR when digested with a proteolytic enzyme human neutrophil elastase. These studies will be extended to TTR proteins from individuals who have pre-symptomatic FAP and carried out on known proportions of normal and variant TTR in the isolated mixture. Understanding the pathogenetic mechanisms involved in the processing of the precursor TTR into amyloid fibrils, they anticipate, will aid in the ultimate goal of defining treatment intervention.

描述：（改编自申请人的摘要）遗传形式 淀粉样变性，家族性淀粉样蛋白多神经病（FAP）是常染色体 与蛋白质突变形式相关的主要遗传条件 经硫代蛋白（TTR，也称为前猫蛋白）。 这是一个罕见的晚期 遗传疾病，导致由于周围和 在第三或第四个十年中的自主神经病和心肌病 生活。 它提出了一个问题，即如何存在异常基因 十年后出生会产生疾病。 活检证明淀粉样蛋白 沉积开始于首次症状之前。 已经确定了淀粉样蛋白前体TTR的六种变体形式。 每个 在正常的127氨基酸中涉及单个氨基酸取代 ttr链。 在28个患有FAP家庭的患者中， 申请人最近确定了一种新变体，并有其他 具有未知类型的变体的家庭。 它们在表型上和 彼此的族裔起源，没有已知的TTR之一 变体。 申请人建议检查其DNA和/或等离子体的 导致淀粉样蛋白沉积并确定的TTR变异 该突变的基因检测技术。 一名患者 纯合突变模式将为检查独特的机会 它的蛋白水解并仅开发对突变蛋白的抗体。 他们计划检验临床症状，年龄变化的假设 在发病时，疾病的进展可能由以外的其他因素来解释 TTR基因中的单核苷酸突变。 他们的初步数据 提示突变体TTR的β形成的根本变化 用蛋白水解酶的人类嗜中性粒细胞弹性酶消化。 这些 研究将扩展到来自具有的个人的TTR蛋白 症状前FAP，并以已知比例的正常和 分离的混合物中的变体TTR。 了解致病性 将前体TTR加工成淀粉样蛋白的机制 他们预料到原纤维将有助于定义的最终目标 治疗干预措施。