Abstract
Mutations in the Aquaporin-2 gene, which encodes a renal water channel, have been shown to cause autosomal nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. Most AQP2 missense mutants in recessive NDI are retained in the endoplasmic reticulum (ER), but AQP2-T125M and AQP2-G175R were reported to be nonfunctional channels unimpaired in their routing to the plasma membrane. In five families, seven novel AQP2 gene mutations were identified and their cell-biologic basis for causing recessive NDI was analyzed. The patients in four families were homozygous for mutations, encoding AQP2-L28P, AQP2-A47V, AQP2-V71M, or AQP2-P185A. Expression in oocytes revealed that all these mutants, and also AQP2-T125M and AQP2-G175R, conferred a reduced water permeability compared with wt-AQP2, which was due to ER retardation. The patient in the fifth family had a G>A nucleotide substitution in the splice donor site of one allele that results in an out-of-frame protein. The other allele has a nucleotide deletion (c652delC) and a missense mutation (V194I). The routing and function of AQP2-V194I in oocytes was not different from wt-AQP2; it was therefore concluded that c652delC, which leads to an out-of-frame protein, is the NDI-causing mutation of the second allele. This study indicates that misfolding and ER retention is the main, and possibly only, cell-biologic basis for recessive NDI caused by missense AQP2 proteins. In addition, the reduced single channel water permeability of AQP2-A47V (40%) and AQP2-T125M (25%) might become of therapeutic value when chemical chaperones can be found that restore their routing to the plasma membrane.
Original language | English |
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Pages (from-to) | 2267-77 |
Number of pages | 11 |
Journal | Journal of the American Society of Nephrology |
Volume | 13 |
Issue number | 9 |
DOIs | |
Publication status | Published - Sep-2002 |
Externally published | Yes |
Keywords
- Amino Acid Sequence
- Animals
- Aquaporin 2
- Aquaporin 6
- Aquaporins/chemistry
- Cell Line
- Cell Membrane/metabolism
- Diabetes Insipidus, Nephrogenic/genetics
- Family Health
- Female
- Genes, Recessive
- Humans
- Infant, Newborn
- Male
- Molecular Sequence Data
- Mutation, Missense
- Oocytes/metabolism
- Pedigree
- Protein Structure, Tertiary
- Protein Transport/genetics
- Water/metabolism
- Xenopus