2002 Global Researcher Conference Proceeding
April 26 - 28, 2002
| Conference: | 2002 Global Researcher Conference |
|---|---|
| Title: | A Novel dominant mutation of the aquaporin-2 gene resulting in partial nephrogenic diabetes insipidus |
| Authors: | Robertson, Gary; Kopp, M.D., Peter |
| Institutions: | Northwestern University Medical School, Northwestern University |
Only 4 of the aquaporin-2 (AQP2) gene mutations reported to cause Nephrogenic Diabetes Insipidus (NDI) are dominant. All of them alter the intracellular C-terminus of AQP2 and 3 of them (a missense mutation that substitutes lysine for glutamic acid at position 258 [E258K] and 2 of 3 deletion-frameshift mutations that alter and extend the C-terminus) cause partial resistance to the antidiuretic effect of vasopressin (VP) (Mulders, Bichet, Rijss et al, 1998; Kuwahara, Iwai, Ooeda et al, 2001). We have found a similar phenotype in a 5 year old girl (SN) with a novel, apparently de novo missense mutation that alters another residue in the same area of AQP2. According to her mother, SN exhibited unusual thirst from birth, was noted to be polyuric at 18 months and was diagnosed with DI at 5 years. When her DI did not respond to standard therapeutic doses of desmopressin, she was referred for further evaluation. There was no history of DI in her mother, father or only sibling (a 9 year old girl) and her physical examination, including height and weight were normal for her age (50th percentile). On ad-libitum intake of fluids, her basal plasma osmolality, sodium, potassium, urea and creatinine were within normal limits. However, her plasma vasopressin (Pvp) was slightly elevated (4.3 pg/ml), her urine osmolality (Uos) was very low (58 mosmol/kg) and her 24 hour urine volume (Uvol) was high (5.9 L or 280 ml/kg), indicating she had moderately severe NDI. When deprived of fluid for 5 hours, she developed mild hypertonic dehydration and raised her Pvp and Uos to 22.3 pg/ml and 220 mosmol/kg. When rehydrated and given a supra-physiologic dose of desmopressin (6.3 µg iv in 20 minutes), her Uos rose to 258 mosmol/kg after 120 minutes, confirming a partial antidiuretic response to stimulation of the AVPR-2 receptor. Sequencing revealed no mutation in the coding region of her AVPR-2 gene but a 761G®A substitution in one allele of the AQP2 gene. This change predicts replacement of arginine with glutamine at position 254 (R254Q) in aquaporin-2.
Treatment of our patient with a sodium restricted diet, potassium supplements and hydrochlorothiazide, 25 mg tid for 4 months increased her basal 24 hour Uos from 54 to 180 mosmol/kg and reduced her Uvol from 5.9 to 2.7 L/day (274 to 128 ml/kg weight/day). When another 6 months of this treatment produced no further improvement in her DI, indomethacin, 25 mg bid, was added. Over the next 12 months, her basal 24 hour Uos rose to 305 mosmol/kg and her Uvol fell to 1.6 L/day (50 ml/kg weight/day) which is the upper limit of the normal range for her age and size. She has continued to grow normally and her plasma sodium, potassium, urea and creatinine are virtually unchanged from pretreatment values.
These findings confirm that another dominant mutation adjacent to the phosphorylation site at serine 256 in the C-terminus of AQP2 also causes NDI that is characterized clinically by partial resistance to the antidiuretic effect of V2R stimulation. They also suggest that the DI resulting from these mutations is exceptionally responsive to control by conventional therapy with thiazide diuretics and prostaglandin synthetase inhibitors.
Robertson and Kopp discovered a new mutation of the AQP2 gene when they were treating a young girl with NDI. This mutation was dominant, which means that the girl needed to carry the defective gene in only a single dose (as opposed to two) for it to have an outwardly apparent effect. The point in the AQP2 where the mutation manifested was at the 254th amino acid residue in the chain of residues that makes up the protein, AQP2. Here there was a glutamine residue where there should have been arginine.
Fortunately, the girl's NDI caused by this mutation was exceptionally responsive to conventional NDI therapy, which involved a sodium restricted diet, potassium supplements, thiazide diuretics and postaglandin synthetase inhibitors. Robertson and Kopp recommended that other physician investigators systematically evaluate this approach to therapy in other NDI patients to determine if its efficacy varies in accordance with the location or type of mutation in the aquaporin-2 or V2 receptor gene.