Abstract

Introduction

Homocystinuria due to cystathionine β-synthase (CBS) deficiency, the most frequent inborn error of sulfur amino acid metabolism, is characterized biochemically by severely elevated homocysteine (Hcy) and related metabolites, such as Hcy-thiolactone and N-Hcy-protein. CBS deficiency reduces life span and causes pathological abnormalities affecting most organ systems in the human body, including the cardiovascular (thrombosis, stroke), skeletal/connective tissue (osteoporosis, thin/non-elastic skin, thin hair), and central nervous systems (mental retardation, seizures), as well as the liver (fatty changes), and the eye (ectopia lentis, myopia). Molecular basis of these abnormalities were largely unknown and available treatments remain ineffective.

Areas covered

Proteomic and transcriptomic studies over the past decade or so, have significantly contributed to our understanding of mechanisms by which the CBS enzyme deficiency leads to clinical manifestations associated with it.

Expert opinion

: Recent findings, discussed in this review, highlight the involvement of dysregulated proteostasis in pathologies associated with CBS deficiency, including thromboembolism, stroke, neurologic impairment, connective tissue/collagen abnormalities, hair defects, and hepatic toxicity. To ameliorate these pathologies, pharmacological, enzyme replacement, and gene transfer therapies are being developed.

中文翻译：

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胱硫醚β-合酶缺乏症的蛋白质组学探索：对临床的意义

摘要

介绍

由于胱硫醚β合酶（CBS）缺乏而引起的高半胱氨酸尿症是硫氨基酸代谢中最常见的先天性错误，其生化特征是高半胱氨酸（Hcy）和相关代谢产物（例如Hcy-硫代内酯和N -Hcy蛋白）严重升高。CBS缺乏症会缩短寿命，并导致影响人体大多数器官系统的病理异常，包括心血管（血栓形成，中风），骨骼/结缔组织（骨质疏松症，皮肤薄/非弹性皮肤，头发稀疏）和中枢神经系统（智力低下，癫痫发作），以及肝脏（脂肪变化）和眼睛（轻度扩张，近视）。这些异常的分子基础在很大程度上是未知的，可用的治疗仍然无效。

覆盖区域

在过去十年左右的时间里，蛋白质组学和转录组学研究为我们对CBS酶缺乏导致相关临床表现的机制的理解做出了重要贡献。

专家意见

：本综述中讨论的最新发现强调了蛋白稳态失调与CBS缺乏相关的病理学的参与，包括血栓栓塞，中风，神经系统损害，结缔组织/胶原蛋白异常，毛发缺陷和肝毒性。为了改善这些病理，正在开发药理学，酶替代和基因转移疗法。