1999 European Regional Conference Proceeding
May 12 - 16, 1999
|Conference:||1999 European Regional Conference|
|Title:||Nephrogenic diabetes insipidus in Italian families|
|Authors:||Albertazzi, Elena; Barbier, Pascaline; Faranda, Sara; Frattini, Annalisa; Vezzoni, Paolo; Bettinelli, Alberto; Procaccio, Mirella; Chini, Bice|
|Institutions:||Consiglio Nazionale delle Ricerche Cellular and Molecular Pharmacology Center, Consiglio Nazionale delle Ricerche Institute of Advanced Biomedical Technologies, Istituto Tecnologie Biomediche Avanzate - ITBA, CNR-ITBA, University of Milan, CNR Institute of Neuroscience|
Chini, et al., studied 17 unrelated Italian families with a clinical history of nephrogenic diabetes insipidus (NDI). The researchers identified mutations in the vasopressin-2 receptor (AVPR2) gene in 14 of the families. Nine of these mutations had not been previously described. Four of these new mutations are predicted to result in a complete loss of function of AVPR2 protein. The remaining five mutations are called missense mutations. This type of mutation causes a replacement of a single amino acid in the AVPR2 protein by an amino acid that is not normally at that point in the sequence of the amino acids that comprise the AVPR2 protein. Nonetheless, this single replacement greatly inhibits the function of the AVPR2s in which they occur. One patient had two missense mutations in his AVPR2 protein.
Chini, et al., used two of the newly identified mutations to see how the structural change in the AVPR2 protein affected its ability to function. The W99R mutation replaced a tryptophan amino acid with an arginine amino acid at amino acid position 99. Mutation A84D replaced an alanine amino acid with an aspartic acid amino acid at position 84. Unlike the majority of AVPR2 gene mutations which are retained inside intracellular compartments and not allowed to travel to their work site on the basolateral membrane, the W99R and A84D receptors are able to get to the basolateral membrane. (The membrane encircles the cell. The bottom and side sections of the membrane are called the basolateral membrane.) There they can bind to the antidiuretic hormone, vasopressin (although at a greatly reduced rate) and become activated.
The researchers tried treating these two mutants with chemical chaperones (proteins which help synthesize, fold and modify the AVPR2 within the cell) in an effort to restore their functional capacity, but the chaperones did not prove effective.