van Leeuwen F, van der Beek E, Seger M, Burbach P, Ivell R
Netherlands Institute for Brain Research, Amsterdam.
Proc Natl Acad Sci U S A. 1989 Aug;86(16):6417-20. doi: 10.1073/pnas.86.16.6417.
A single-base deletion in the single-copy vasopressin gene is the cause of diabetes insipidus in the homozygous Brattleboro rat (di/di). It results in the synthesis of an altered vasopressin precursor of which the axonal transport is blocked. Paradoxically, a small number of solitary hypothalamic neurons displays all the immunoreactivities of the wild-type vasopressin precursor (i.e., vasopressin, neurophysin, and a glycopeptide). In the present paper we provide evidence that these neurons have undergone a switch to a genuine heterozygous (di/+) phenotype; i.e., they contain the immunoreactivities of both the wild-type and the mutated vasopressin precursors. In the neural lobe, glycopeptide fibers are also present, showing that axonal transport of the wild-type precursor is restored. Moreover, the number of neurons displaying this di/+ phenotype increases markedly and in a linear way (from 0.1% up to 3% of the vasopressin cells) with age. These findings indicate that after mitotic division has ceased, genomic alterations occur in somatic neurons in vivo. The molecular event generating the di/+ phenotype in the di/di animal could involve a somatic intrachromosomal gene conversion between the homologous exons of the vasopressin and the related oxytocin genes.
单拷贝抗利尿激素基因中的单碱基缺失是纯合布拉特洛维大鼠（di/di）尿崩症的病因。这导致合成一种改变的抗利尿激素前体，其轴突运输被阻断。矛盾的是，少数孤立的下丘脑神经元显示出野生型抗利尿激素前体的所有免疫反应性（即抗利尿激素、神经垂体素和一种糖肽）。在本文中，我们提供证据表明这些神经元已转变为真正的杂合（di/+）表型；即它们含有野生型和突变型抗利尿激素前体的免疫反应性。在神经叶中，也存在糖肽纤维，表明野生型前体的轴突运输得以恢复。此外，显示这种di/+表型的神经元数量随着年龄的增长而显著且呈线性增加（从抗利尿激素细胞的0.1%增加到3%）。这些发现表明，有丝分裂停止后，体内的体细胞神经元会发生基因组改变。在di/di动物中产生di/+表型的分子事件可能涉及抗利尿激素基因和相关催产素基因同源外显子之间的体细胞染色体内基因转换。
