Familial forms of diabetes insipidus: clinical and molecular characteristics

Abstract

Over the past two decades, the genetic and molecular basis of familial forms of diabetes insipidus has been elucidated. Diabetes insipidus is a clinical syndrome characterized by the excretion of abnormally large volumes of diluted urine (polyuria) and increased fluid intake (polydipsia). The most common type of diabetes insipidus is caused by lack of the antidiuretic hormone arginine vasopressin (vasopressin), which is produced in the hypothalamus and secreted by the neurohypophysis. This type of diabetes insipidus is referred to here as neurohypophyseal diabetes insipidus. The syndrome can also result from resistance to the antidiuretic effects of vasopressin on the kidney, either at the level of the vasopressin 2 receptor or the aquaporin 2 water channel (which mediates the re-absorption of water from urine), and is referred to as renal or nephrogenic diabetes insipidus. Differentiation between these two types of diabetes insipidus and primary polydipsia can be difficult owing to the existence of partial as well as complete forms of vasopressin deficiency or resistance. Seven different familial forms of diabetes insipidus are known to exist. The clinical presentation, genetic basis and cellular mechanisms responsible for them vary considerably. This information has led to improved methods of differential diagnosis and could provide the basis of new forms of therapy.

Hereditary nephrogenic diabetes insipidus in Japanese patients: analysis of 78 families and report of 22 new mutations in AVPR2 and AQP2

“…These data provide clear evidence for the general assumption that 90 % of cases are caused by AVPR2 and 10 % are caused by AQP2 mutations [1,3]. These data also indicate that the genetic mechanisms for congenital NDI are the same in the Japanese population.…”

“…This missorting is confirmed in knockin mice harboring a human C-terminal deletion mutation (c.763-772del) [32]. It is interesting that these deletion mutations are observed more often that missense mutations in Japanese patients, which is different from the frequencies in a total global summary [3,20].…”

“…Therefore, NDI patients manifest polyuria and polydipsia. The hereditary (congenital) form of NDI is relatively rare, and is known to be caused by mutations in two genes, the arginine vasopressin type 2 receptor (AVPR2) and the water channel aquaporin 2 (AQP2) [1][2][3][4]. These two genes encode two membrane proteins that are oppositely located at the basolateral and apical membranes of the collecting duct principal cells, respectively, and constitute the fundamental components of urine concentrating machinery [5,6].…”

“…The AQP2 gene is located on chromosome 12 (12q13.12), and NDI caused by AQP2 mutations shows both autosomal recessive and dominant inheritance (OMIM 125800, 107777) [7,8]. Several review papers have claimed that about 90 % of NDI patients carry AVPR2 mutations and about 10 % carry AQP2 mutations; however, actual data in support of this estimate have not been shown [1,3]. It is also unknown whether the genetic causes of NDI vary among different ethnic groups.…”

A Copeptin-Based Classification of the Osmoregulatory Defects in the Syndrome of Inappropriate Antidiuresis

“…Still, this type of defect is particularly interesting because it raises the question of whether affected patients are capable of responding to treatment with AVPR2-blocking agents. 6,25 Intriguingly, one patient in this group (patient 37) was successfully treated with tolvaptan, resulting in sustained normonatremia. Thus, it is conceivable that individual patients with type D SIAD become hypersensitive to the antidiuretic effects of AVP, 26 possibly as a result of upregulated AVP2R expression.…”