1998 Global Conference Proceeding
March 02 - 04, 1998
| Conference: | 1998 Global Conference |
|---|---|
| Title: | Diversity of Nephrogenic Diabetes Insipidus Mutations and Importance of Early Recognition and Treatment |
| Authors: | Bichet, Daniel G.; Lonergan, Michele; Arthus, Marie-Francoise; Crumley, M. Joyce; Turner, Maria S.; Morgan, Kenneth; Fujiwara, T. Mary |
| Institutions: | Hopital du Sacre-Coeur de Montreal, Montreal General Hospital Research Institute, Hopital du Sacre-Coeur de Montreal et Universite de Montreal, Montreal General Hospital |
In nephrogenic diabetes insipidus, the kidney is unable to concentrate urine despite normal or elevated concentrations of the antidiuretic hormone arginine vasopressin (AVP). In congenital nephrogenic diabetes insipidus (NDI), the obvious clinical manifestations of the disease, that is polyuria and polydipsia, are present at birth and need to be immediately recognized to avoid severe episodes of dehydration. Most (> 90%) of congenital NDI patients have mutations in the AVPR2 gene, the Xq28 gene coding for the vasopressin V2 (antidiuretic) receptor. In less than 10 % of the families studied, congenital NDI has an autosomal recessive inheritance and mutations have been identified in the aquaporin-2 gene (AQP2) located in chromosome region 12q13, i.e. the vasopressin-sensitive water channel.
Eighty-four different putative disease-causing mutations in the AVPR2 gene have now been published in 124 unrelated families with X-linked nephrogenic diabetes insipidus and a total of 117 distinct mutations are now listed in our database. The diversity of AVPR2 mutations found in many ethnic groups (Caucasians, Japanese, Afro-Americans, Africans) and the rareness of the disease is consistent with an X-linked recessive disease that in the past was lethal for male patients and was balanced by recurrent mutation. In X-linked NDI, loss of mutant alleles from the population occurs because of the higher mortality of affected males compared with healthy males, whereas gain of mutant alleles occurs by mutation. If affected males with a rare X-linked recessive disease do not reproduce and if mutation rates are equal in mothers and fathers, then, at genetic equilibrium, one-third of new cases of affected males will be due to new mutations. We and others have described ancestral mutations, de novo mutations, and potential mechanisms of mutagenesis.
Identification of the molecular defects underlying congenital NDI is of immediate clinical significance, allowing diagnosis by DNA analysis. We encourage physicians who follow families with X-linked and non X-linked NDI to recommend molecular genetic analysis, because early diagnosis and treatment of affected infants can avert the physical and mental retardation associated with episodes of dehydration. Diagnosis of X-linked NDI was accomplished by mutation testing of cultured amniotic cells (n=4), chorionic villus samples (n=2) or cord blood obtained at birth (n=10) in 16 of our patients. Eight males were found to bear mutant sequences, six males were not affected and two girls were not carriers. The affected patients were immediately treated with abundant water intake, a low sodium diet and hydrochlorothiazide. They never experienced episodes of dehydration, and their physical and mental development is normal.