Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, USA.
J Biol Chem. 2011 Mar 18;286(11):9196-204. doi: 10.1074/jbc.M110.192351. Epub 2011 Jan 5.
Human norepinephrine (NE) deficiency (or dopamine β-hydroxylase (DBH) deficiency) is a rare congenital disorder of primary autonomic failure, in which neurotransmitters NE and epinephrine are undetectable. Although potential pathogenic mutations, such as a common splice donor site mutation (IVS1+2T→C) and various missense mutations, in NE deficiency patients were identified, molecular mechanisms underlying this disease remain unknown. Here, we show that the IVS1+2T→C mutation results in a non-detectable level of DBH protein production and that all three missense mutations tested lead to the DBH protein being trapped in the endoplasmic reticulum (ER). Supporting the view that mutant DBH induces an ER stress response, exogenous expression of mutant DBH dramatically induced expression of BiP, a master ER chaperone. Furthermore, we found that a pharmacological chaperone, glycerol, significantly rescued defective trafficking of mutant DBH proteins. Taken together, we propose that NE deficiency is caused by the combined abnormal processing of DBH mRNA and defective protein trafficking and that this disease could be treated by a pharmacological chaperone(s).
人类去甲肾上腺素 (NE) 缺乏症（或多巴胺 β-羟化酶 (DBH) 缺乏症）是一种罕见的原发性自主神经衰竭的先天性疾病，其中神经递质 NE 和肾上腺素无法检测到。尽管已经确定了 NE 缺乏症患者中存在潜在的致病突变，例如常见的剪接供体位点突变（IVS1+2T→C）和各种错义突变，但该疾病的分子机制仍不清楚。在这里，我们表明 IVS1+2T→C 突变导致 DBH 蛋白的产生无法检测到，并且测试的所有三种错义突变都导致 DBH 蛋白被困在内质网 (ER) 中。支持突变的 DBH 诱导内质网应激反应的观点，外源性表达突变的 DBH 显著诱导内质网伴侣蛋白 BiP 的表达。此外，我们发现一种药理学伴侣，甘油，可显著挽救突变的 DBH 蛋白的缺陷运输。总之，我们提出 NE 缺乏症是由 DBH mRNA 的异常加工和蛋白质运输缺陷共同引起的，并且可以通过药理学伴侣治疗这种疾病。
