Sonnemans M S, Evans D A, Burbach J P, Van Leeuwen F W
Graduate School of Neurosciences, Netherlands Institute for Brain Research, Amsterdam, The Netherlands.
Neuroscience. 1996 May;72(1):225-31. doi: 10.1016/0306-4522(95)00550-1.
A single base deletion (delta G) in the vasopressin gene is the cause of diabetes insipidus in the homozygous Brattleboro rat (di/di). The resulting frameshift leads to the expression of an aberrant vasopressin precursor which is unable to enter the secretory pathway, thereby preventing vasopressin biosynthesis. In a small number of solitary magnocellular hypothalamic neurons within the supraoptic and paraventricular nuclei, the reading frame is restored by a dinucleotide (delta GA) frameshift mutation, at two separate GAGAG motifs downstream of the original G-deletion. This results in two + 1 di-vasopressin precursors that are still partially mutated within the neurophysin region. The present study provides immunocytochemical evidence which demonstrates that, within magnocellular solitary neurons of the supraoptic and paraventricular nuclei of the di/di rat, the + 1 di-vasopressin precursors can enter the secretory pathway followed by their enzymatic processing into vasopressin during axonal transport to the neural lobe. However, the cellular characteristics of biosynthesis are different from those of wild-type rats. Immunoelectron microscopical localization of vasopressin gene products in the neural lobe of did/di rats revealed their presence in neurosecretory granules, the diameter of which is intermediate (116 nm) between those of the neurosecretory granules in the di/di (80-100 nm) and wild-type (160 nm) rats.
血管加压素基因中的单个碱基缺失（ΔG）是纯合布拉德福德大鼠（di/di）患尿崩症的原因。由此产生的移码导致异常血管加压素前体的表达，该前体无法进入分泌途径，从而阻止血管加压素的生物合成。在视上核和室旁核内少数孤立的大细胞下丘脑神经元中，阅读框通过二核苷酸（ΔGA）移码突变得以恢复，该突变发生在原始G缺失下游的两个独立的GAGAG基序处。这产生了两种+1双血管加压素前体，它们在神经垂体激素区域内仍有部分突变。本研究提供了免疫细胞化学证据，证明在di/di大鼠视上核和室旁核的大细胞孤立神经元内，+1双血管加压素前体可以进入分泌途径，随后在轴突运输至神经叶的过程中经酶加工成血管加压素。然而，生物合成的细胞特征与野生型大鼠不同。对di/di大鼠神经叶中血管加压素基因产物的免疫电子显微镜定位显示，它们存在于神经分泌颗粒中，其直径介于di/di大鼠（80 - 100 nm）和野生型大鼠（160 nm）神经分泌颗粒的直径之间（116 nm）。
