TRANSTHYRETIN IN FAMILIAL AMYLOIDOTIC POLYNEUROPHATHY

描述：（改编自申请人的摘要）遗传形式 家族性淀粉样变性多发性神经病（FAP）是淀粉样变性的一种常染色体遗传病， 与蛋白质突变形式相关的显性遗传状况 甲状腺素运载蛋白（TTR，也称为前白蛋白）。 这是一种罕见的迟发性 遗传性疾病，由于外周和 自主神经病变和心肌病在第三或第四个十年 生活 这就提出了一个问题，即一个存在于人类染色体上的异常基因， 出生十年后就会产生疾病 活检证明淀粉样蛋白 沉积就在第一次出现症状之前开始。 淀粉样蛋白前体TTR的六种变体形式已被鉴定。 每个 包括在正常的127个氨基酸中的单个氨基酸取代 TTR链 在来自28个FAP家族的患者中， 申请人最近鉴定了一种新的变体， 具有未知类型变体的家族。 它们在表型上不同， 种族起源，没有一个已知的TTR 变体。 申请人建议检查他们的DNA和/或血浆， TTR变异导致淀粉样蛋白沉积， 基因突变的基因检测技术。 1例患者 纯合突变模式将提供独特的机会， 它的蛋白水解和开发抗体只突变蛋白。 他们计划测试一个假设，即临床症状、年龄 发病时，疾病进展可能由以下因素解释， TTR基因的单核苷酸突变 他们的初步数据 表明突变TTR的β形成发生了根本性的变化， 用蛋白水解酶人中性粒细胞弹性蛋白酶消化。 这些 研究将扩展到TTR蛋白质的个人谁有 症状前FAP，并进行了已知比例的正常和 分离的混合物中的TTR变体。 了解病因 TTR前体加工成淀粉样蛋白的机制 他们预计，原纤维将有助于最终确定 治疗干预。

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.