An impaired routing of wild-type aquaporin-2 after tetramerization with an aquaporin-2 mutant explains dominant nephrogenic diabetes insipidus

被引:159
作者
Kamsteeg, EJ [1 ]
Wormhoudt, TAM [1 ]
Rijss, JPL [1 ]
van Os, CH [1 ]
Deen, PMT [1 ]
机构
[1] Univ Nijmegen, Dept Cell Physiol, NL-6500 HB Nijmegen, Netherlands
关键词
disease; oligomerization; oocytes; recessive;
D O I
10.1093/emboj/18.9.2394
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Autosomal recessive and dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin, are caused by mutations in the aquaporin-2 (AQP2) gene. Missense AQP2 proteins in recessive NDI have been shown to be retarded in the endoplasmic reticulum, whereas AQP2-E258K, an AQP2 mutant in dominant NDI, was retained in the Golgi complex. In this study, we identified the molecular mechanisms underlying recessive and dominant NDI, Sucrose gradient centrifugation of rat and human kidney proteins and subsequent immunoblotting revealed that AQP2 forms homotetramers. When expressed in oocytes, wild-type AQP2 and AQP2-E258K also formed homotetramers, whereas AQP2-R187C, a mutant in recessive NDI, was expressed as a monomer. Upon co-injection, AQP2-E258K, but not AQP2-R187C, was able to heterotetramerize with wild-type AQP2, Since an AQP monomer is the functional unit and AQP2-E258K is a functional but misrouted water channel, heterotetramerization of AQP2-E258K with wild-type AQP2 and inhibition of further routing of this complex to the plasma membrane is the cause of dominant NDI, This case of NDI is the first example of a dominant disease in which the 'loss-of-function' phenotype is caused by an impaired routing rather than impaired function of the wild-type protein.
引用
收藏
页码:2394 / 2400
页数:7
相关论文
共 43 条
[1]   Mutations in the extracellular domain cause RET loss of function by a dominant negative mechanism [J].
Cosma, MP ;
Cardone, M ;
Carlomagno, F ;
Colantuoni, V .
MOLECULAR AND CELLULAR BIOLOGY, 1998, 18 (06) :3321-3329
[2]  
Deen PMT, 1996, J AM SOC NEPHROL, V7, P836
[3]   WATER CHANNELS ENCODED BY MUTANT AQUAPORIN-2 GENES IN NEPHROGENIC DIABETES-INSIPIDUS ARE IMPAIRED IN THEIR CELLULAR ROUTING [J].
DEEN, PMT ;
CROES, H ;
VANAUBEL, RAMH ;
GINSEL, LA ;
VANOS, CH .
JOURNAL OF CLINICAL INVESTIGATION, 1995, 95 (05) :2291-2296
[4]   REQUIREMENT OF HUMAN RENAL WATER CHANNEL AQUAPORIN-2 FOR VASOPRESSIN-DEPENDENT CONCENTRATION OF URINE [J].
DEEN, PMT ;
VERDIJK, MAJ ;
KNOERS, NVAM ;
WIERINGA, B ;
MONNENS, LAH ;
VANOS, CH ;
VANOOST, BA .
SCIENCE, 1994, 264 (5155) :92-95
[5]   AQUAPORIN-3 WATER CHANNEL LOCALIZATION AND REGULATION IN RAT-KIDNEY [J].
ECELBARGER, CA ;
TERRIS, J ;
FRINDT, G ;
ECHEVARRIA, M ;
MARPLES, D ;
NIELSEN, S ;
KNEPPER, MA .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL FLUID AND ELECTROLYTE PHYSIOLOGY, 1995, 269 (05) :F663-F672
[6]   SUBUNIT-DEPENDENT ASSEMBLY OF INWARD-RECTIFIER K+ CHANNELS [J].
GLOWATZKI, E ;
FAKLER, G ;
BRANDLE, U ;
REXHAUSEN, U ;
ZENNER, HP ;
RUPPERSBERG, JP ;
FAKLER, B .
PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, 1995, 261 (1361) :251-261
[7]  
HOEK AN, 1991, J BIOL CHEM, V266, P16633
[8]   PROTEIN OLIGOMERIZATION IN THE ENDOPLASMIC-RETICULUM [J].
HURTLEY, SM ;
HELENIUS, A .
ANNUAL REVIEW OF CELL BIOLOGY, 1989, 5 :277-307
[9]  
Jennings Michael L., 1992, Journal of General Physiology, V100, p21A
[10]  
JUNG JS, 1994, J BIOL CHEM, V269, P14648