1999 European Regional Conference Proceeding

May 12 - 16, 1999

Line
Conference: 1999 European Regional Conference
Title: Congenital (present a birth) severe diabetes insipidus. Most patients have nephrogenic diabetes insipidus (NDI), but some patients have autosomal recessive central (neurogenic) diabetes insipidus
Authors: Bichet, Daniel G.; Fujiwara, T. Mary
Institutions: Hopital du Sacre-Coeur de Montreal, Montreal General Hospital
Line
Bichet

Most (90%) of congenital NDI patients have mutations in the AVPR2 gene, the Xq28 gene coding for the vasopressin V2 receptor.

In less than 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant inheritance and mutations have been identified in the aquaporin-2 gene (AQP2) located in chromosome region 12q13, i.e. the vasopressin-sensitive water channel. To date, 155 putative disease-causing AVPR2 mutations have been identified in 239 NDI families. Half of the mutations are missense mutations. Frameshift mutations due to nucleotide deletions or insertions (27%), nonsense mutations (11%), large deletions (5%), inframe deletion or insertions (4%), splice-site mutations (2%), and one complex mutation account for the remainder of the mutations. Mutations have been identified in every domain, but on a per nucleotide basis, about twice as many mutations occur in transmembrane domains compared to the extracellular or intracellular domains. A recent estimate of the incidence of X-linked NDI in the general population is about 1 in 152,000 male births. This estimate was based on the ascertainment of three affected boys who were born in the Province of Quebec, Canada, during the 10-year period 1988-1997 among 455,000 male births. Most of these AVPR2 mutations are inducing polyuro-polydipsic manifestations observed in the first week of life. Only three AVPR2 mutations (D85N, G201D, P322S) have been associated with a mild phenotype. Males bearing these missense mutations were identified later in life and the classical episodes of dehydration were less severe. To date, patients in 13 of 19 families with autosomal recessive NDI were homozygous for an AQP2 mutation and six families have been identified with autosomal dominant NDI due to heterozygosity for an AQP2 mutation. Finally, we have identified two families with autosomal recessive neurogenic diabetes insipidus. In these families, the patients were homozygous or compound heterozygotes for prepro-AVP-NPII mutations. These affected patients are characterized phenotypically by severe and early onset of polyuria, polydipsia, and dehydration. In conclusion, early hereditary diabetes insipidus can be nephrogenic or neurogenic.

Ninety percent of the cases of congenital nephrogenic diabetes insipidus (NDI) are the result of mutations of the vasopressin-2 (AVPR2) gene (X-linked NDI). The remaining ten percent are due to mutations of the aquaporin-2 (AQP2) gene. The incidence of X-linked NDI in the general population is about one in 152,000 male births. One hundred fifty-five different AVPR2 gene mutations have been identified in 239 NDI families. Half of the mutations are missense mutations. The other fifty percent are made up of frameshift and nonsense mutations, large deletions, inframe deletions or insertions, splice-site mutations and one complex mutation. Twice as many mutations occur in the transmembrane domain portions of the AVPR2 protein as anywhere else on the protein.

Most infants born with AVPR2 mutations display the symptoms of NDI in the first days of life. Only three AVPR2 mutations have been associated with mild symptoms. Thirteen of the 19 families with autosomal NDI (caused by mutations of the aquaporin-2 gene on chromosome 12) transmitted the disorder in an autosomal recessive fashion. Bichet, et al., identified two families with a different type of diabetes insipidus called neurogenic diabetes insipidus that was transmitted in an autosomal recessive fashion. These patients also experienced polyuria, polydipsia and dehydration in the first days of life.