Two Novel Aquaporin-2 Mutations Responsible for Congenital Nephrogenic Diabetes Insipidus in Chinese Families
| Title: | Two Novel Aquaporin-2 Mutations Responsible for Congenital Nephrogenic Diabetes Insipidus in Chinese Families |
|---|---|
| Authors: | Lin, Shih-Hua; Bichet, Daniel G.; Sasaki, Sei; Kuwahara, Michio; Arthus, Marie-Francoise; Lonergan, Michele; Lin, Yuh-Feng |
| Publisher: | Journal of Clinical Endocrinology and Metabolism |
| Date Published: | June 01, 2002 |
| Reference Number: | 552 |
Mutations in the aquaporin-2 gene (AQP2), encoding the vasopressin-regulated water channel of the renal collecting duct, are responsible for the autosomal recessive or dominant forms of congenital nephrogenic diabetes insipidus. We describe two new families with normal hypotensive and coagulation responses following the administration of desamino-8-D-arginine AVP, a clinical suggestion of normal vasopressin-2 receptors. The patients were compound heterozygotes for point mutations at nucleotide position 170 (CAG to CCG; Q57P) and at position 299 (GGA to GTA; G100V) in exon 1 of the AQP2 gene. Expression of the G57P and G100V AQP2 proteins in Xenopus oocytes showed only 1.3-fold and 1.2-fold increase, respectively, in the water permeability in contrast to 8.0-fold increase in oocytes injected with wild-type cRNA. Immunoblots of oocyte lysate revealed the intensities of the 29-kDa bands were comparable among oocytes injected with wild-type and mutant cRNAs. Immunocytochemistry showed the plasma membrane was not stained in oocytes injected with cRNA of Q57P and of G100V. These results provide evidence that the Q57P and G100V mutations in congenital nephrogenic diabetes insipidus are attributable to the misrouting of AQP2.
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
Mutations of the AQP2 gene are responsible for 10% of the cases of inherited NDI, and only 19 AQP2 mutations have been reported in scientific literature. Lin, et al., report two previously unreported AQP2 mutations responsible for inherited NDI in two unrelated Chinese families. The NDI patients in each family had the same two new mutations.
The first mutation is called Q57P. That indicates that the amino acid proline (P) was in a position that should have been occupied by the amino acid glutamine (Q) in the AQP2 protein. The second mutation is called G100V. That means that a valine (V) amino acid is in the position that should have been occupied by a glycine (G) amino acid in the AQP2.
The researchers tested to see how the structural change caused by the mutations affected the mutant AQP2's ability to function. After determining that the laboratory cell cultures injected with the mutant AQPf2s showed little increase in their ability to allow water across the cell membranes, the researchers suggested that the mutant AQP2s were retained in the cell interior in a quality control section of the cell called the endoplasmic reticulum (ER). Thus, they were not able to travel to the cell membranes to make them more water permeable.