常染色体显性遗传性神经垂体性尿崩症的分子基础。内质网内突变型血管加压素前体积累所导致的细胞毒性。
Molecular basis of autosomal dominant neurohypophyseal diabetes insipidus. Cellular toxicity caused by the accumulation of mutant vasopressin precursors within the endoplasmic reticulum.
作者信息
Ito M, Jameson J L, Ito M
机构信息
Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
出版信息
J Clin Invest. 1997 Apr 15;99(8):1897-905. doi: 10.1172/JCI119357.
Abstract
Mutations in the arginine vasopressin (AVP) gene cause autosomal dominant familial neurohypophyseal diabetes insipidus (FNDI). The dominant inheritance pattern has been postulated to reflect neuronal toxicity of the mutant proteins, but the mechanism for such cytotoxicity is unknown. In this study, wild-type or several different mutant AVP genes were stably expressed in neuro2A neuroblastoma cells. When cells were treated with valproic acid to induce neuronal differentiation, each of the mutants caused reduced viability. Metabolic labeling revealed diminished intracellular trafficking of mutant AVP precursors and confirmed inefficient secretion of immunoreactive AVP. Immunofluorescence studies demonstrated marked accumulation of mutant AVP precursors within the endoplasmic reticulum. These studies suggest that the cellular toxicity in FNDI may be caused by the intracellular accumulation of mutant precursor proteins.
摘要
精氨酸加压素（AVP）基因突变会导致常染色体显性遗传性家族性神经垂体性尿崩症（FNDI）。显性遗传模式被认为反映了突变蛋白的神经毒性，但这种细胞毒性的机制尚不清楚。在本研究中，野生型或几种不同的突变型AVP基因在Neuro2A神经母细胞瘤细胞中稳定表达。当用丙戊酸处理细胞以诱导神经元分化时，每种突变体都会导致细胞活力下降。代谢标记显示突变型AVP前体的细胞内运输减少，并证实免疫反应性AVP的分泌效率低下。免疫荧光研究表明内质网内突变型AVP前体明显积聚。这些研究表明，FNDI中的细胞毒性可能是由突变前体蛋白的细胞内积聚引起的。
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