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Functional recovery of AQP2 recessive mutations through hetero‐oligomerization with wild‐type counterpart (1133.2)
Author(s) -
El Tarazi Abdulah,
Lussier Yoann,
Da Cal Sandra,
Bissonnette Pierre,
Bichet Daniel
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1133.2
Subject(s) - aquaporin 2 , nephrogenic diabetes insipidus , mutant , homomeric , reabsorption , xenopus , heterozygote advantage , wild type , microbiology and biotechnology , transfection , mutation , chemistry , kidney , aquaporin , hek 293 cells , biology , gene , genetics , allele , water channel , mechanical engineering , protein subunit , engineering , inlet
Mutations in Aquaporin‐2 (AQP2) induce nephrogenic diabetes insipidus (NDI), a water reabsorption defect of the kidney challenging water homeostasis. While the accepted NDI model claims that recessive (rec) mutations are misfolded and monomeric by nature, the partial activity (Pf= 15‐25% of wt‐AQP2) found with some mutations (D150E, V24A) challenges this notion, and even suggest the presence for mixed wt/rec heteromers in heterozygotes. We have tested this hypothesis in Xenopus oocytes and showed that not only do wt/rec associate (co‐IP assays), but activity of the rec‐AQP2 mutant is shown to be mostly restored (63‐100% of wt‐AQP2) in the process. Also, using bidirectional vectors for dual transfection in cell lines, we find a recovery of targeting for rec‐AQP2 when in presence of wt‐AQP2. Finally, the negative results found when analyzing the strictly monomeric R187C mutant support the notion that the functional recovery of (at least some) rec‐AQP2 mutants is secondary to wt/rec heteromerization. In conclusion, we show that recessive mutations may be functionally recovered through wt/rec oligomerization, contributing to the overall activity in heterozygotes, a notion which could be relevant to all homomeric proteins.