Differential cellular handling of defective arginine vasopressin (AVP) prohormones in cells expressing mutations of the AVP gene associated with autosomal dominant and recessive familial neurohypophyseal diabetes insipidus

被引:33
作者
Christensen, JH
Siggaard, C
Corydon, TJ
Robertson, GL
Gregersen, N
Bolund, L
Rittig, S
机构
[1] Aarhus Univ Hosp, Pediat Res Lab, DK-8200 Aarhus N, Denmark
[2] Aarhus Univ Hosp, Dept Pediat, DK-8200 Aarhus N, Denmark
[3] Aarhus Univ Hosp, Res Unit Mol Med, DK-8200 Aarhus N, Denmark
[4] Aarhus Univ, Dept Human Genet, DK-8000 Aarhus C, Denmark
[5] Northwestern Univ, Sch Med, Dept Med, Chicago, IL 60611 USA
关键词
D O I
10.1210/jc.2003-031813
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
An unusual mutation in the arginine vasopressin (AVP) gene, predicting a P26L amino acid substitution of the AVP prohormone, is associated with autosomal recessive familial neurohypophyseal diabetes insipidus (FNDI). To investigate whether the cellular handling of the P26L prohormone differed from that of the Y21H prohormone associated with autosomal dominant inheritance of FNDI, the mutations were examined by heterologous expression in cell lines. Immunoprecipitation demonstrated retarded processing and secretion of the Y21H prohormone, whereas the secretion of the P26L prohormone seemed to be unaffected. Confocal laser scanning microscopy showed accumulation of the Y21H prohormone in the endoplasmic reticulum, whereas the P26L prohormone and/or processed products were localized in secretory granules in the cellular processes. RIA analysis showed reduced amounts of immunoreactive Y21H-AVP and P26L-AVP in the cell culture medium. Thus, the recessive mutation does not seem to affect the intracellular trafficking but rather the final processing of the prohormone. Our results provide an important negative control in support of the hypothesis that autosomal dominant inheritance of FNDI is caused by mutations in the AVP gene that alter amino acid residues important for folding and/or dimerization of the neurophysin II moiety of the AVP prohormone and subsequent transport from the endoplasmic reticulum.
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页码:4521 / 4531
页数:11
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