Kim J K, Schrier R W
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.
Proc Assoc Am Physicians. 1998 Sep-Oct;110(5):380-6.
The arginine vasopressin (AVP) precursor gene of mammals contains three exons encoding the principal domains of the polyprotein precursor, including vasopressin (exon A), neurophysin (exon B), and glycopeptide (exon C). The AVP precursor (preprohormone) is processed and transported through the endoplasmic reticulum (ER), Golgi apparatus, and secretory vesicles, and finally, mature AVP is secreted from the posterior pituitary into the circulation. The exact steps of these processes during AVP translation and posttranslation events are not yet well elucidated. Defects in peptide processing are associated with several genetic disorders, including central diabetes insipidus (CDI). In the Brattleboro rat with CDI, the mRNA and protein of AVP are present in the hypothalamus, but no circulating AVP is detectable, thus suggesting a processing defect, transport defect, or both. The mutated AVP gene precursor of Brattleboro rat has a deletion of a single base, guanine, in the neurophysin coding region that leads to a frameshift resulting in the loss of the normal stop codon. It has been reported that the mutated precursor is trapped in the ER and does not reach the Golgi apparatus. Recent studies examined AVP secretion in cultured COS cells transfected with various constructs from wild-type and mutated Brattleboro AVP gene precursors. The wild-type in vitro studies demonstrated that intact neurophysin, but not the glycoprotein coding region, is necessary for normal AVP processing and secretion. Next, the results demonstrated that the guanine defect in the neurophysin coding region and the prolonged C-terminus accounted for the processing defect in the Brattleboro rat with CDI. These defects no doubt impair the folding and configuration necessary for normal processing of the AVP gene precursor in the ER. In hereditary CDI in humans, the majority of the mutations have also been shown to occur in the neurophysin coding region. However, in contrast to the recessive defect in the Brattleboro rat, in human CDI, neurotoxicity and denigration of the magnocellular neurons have been observed, and dominant inheritance occurs. Moreover, all mutations are missense, nonsense, or deletions in human CDI rather than the shift in reading frame and preserved neurons that is observed with the Brattleboro rat. Thus, the results from studies in the Brattleboro rat may only be partially applicable to hereditary CDI in humans.
哺乳动物的精氨酸加压素（AVP）前体基因包含三个外显子，它们编码多蛋白前体的主要结构域，包括加压素（外显子A）、神经垂体素（外显子B）和糖肽（外显子C）。AVP前体（前激素原）经过加工后通过内质网（ER）、高尔基体和分泌囊泡进行运输，最终，成熟的AVP从垂体后叶分泌到循环系统中。在AVP翻译和翻译后事件期间，这些过程的确切步骤尚未得到充分阐明。肽加工缺陷与多种遗传疾病相关，包括中枢性尿崩症（CDI）。在患有CDI的布拉德福德大鼠中，下丘脑存在AVP的mRNA和蛋白质，但检测不到循环中的AVP，因此提示存在加工缺陷、运输缺陷或两者皆有。布拉德福德大鼠的突变AVP基因前体在神经垂体素编码区缺失了单个碱基鸟嘌呤，导致移码突变，从而失去了正常的终止密码子。据报道，突变的前体被困在内质网中，无法到达高尔基体。最近的研究检测了用野生型和突变型布拉德福德AVP基因前体的各种构建体转染的培养COS细胞中的AVP分泌情况。体外野生型研究表明，完整的神经垂体素而非糖蛋白编码区对于正常的AVP加工和分泌是必需的。接下来，结果表明神经垂体素编码区的鸟嘌呤缺陷和延长的C末端导致了患有CDI的布拉德福德大鼠的加工缺陷。这些缺陷无疑损害了内质网中AVP基因前体正常加工所需的折叠和构象。在人类遗传性CDI中，大多数突变也已被证明发生在神经垂体素编码区。然而，与布拉德福德大鼠的隐性缺陷不同，在人类CDI中，已观察到巨细胞神经元的神经毒性和变性，并且呈显性遗传。此外，在人类CDI中，所有突变都是错义突变、无义突变或缺失，而不是像布拉德福德大鼠那样观察到的阅读框移位和神经元保留。因此，在布拉德福德大鼠中的研究结果可能仅部分适用于人类遗传性CDI。
