A Null Mutation in the Vasopressin V2 Receptor Gene (AVPR2) Associated with Nephrogenic Diabetes Insipidus in the Hopewell Kindred

Title: A Null Mutation in the Vasopressin V2 Receptor Gene (AVPR2) Associated with Nephrogenic Diabetes Insipidus in the Hopewell Kindred
Authors: Holtzman, M.D., Eliezer J.; Kolakowski, PhD, Lee F.; O'Brien, David; Crawford, M.D., John D.; Ausiello, M.D., Dennis A.
Publisher: Human Molecular Genetics
Date Published: August 01, 1993
Reference Number: 125
Congenital nephrogenic diabetes insipidus (DIR) is a rare X-linked hereditary disorder in which the renal collecting duct is unresponsive to arginine vasopressin; thus the urine is consistently hypotonic to plasma. Recently, the association between the V2 receptor gene (AVPR2) and DIR has been proven. We have determined the gene sequence of four family members, from three generations, of a large North American family with CNDI who were originally part of the study used to formulate the Hopewell hypothesis. It had been proposed that a single DIR gene defect was introduced to North America by a member of an Ulster Scot kindred arriving on the ship Hopewell in 1761. DNA sequencing of the AVPR2 has identified a single base transversion from G-->A which changes tryptophan 71 to a stop codon in affected patients. This point mutation causes a truncation of the receptor leading to an essentially null allele. These data and other recently described mutations in the AVPR2 in North American pedigrees, descended from Ulster Scot ancestors and other origins, make the assertion of a founder effect proposed in the Hopewell hypothesis invalid.

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)

Congenital nephrogenic diabetes insipidus (NDI) is a rare, X-linked hereditary disorder characterized by the kidney's inability to respond to the antidiuretic hormone, arginine vasopressin (AVP). As a result, the NDI patient is unable to let water be reabsorbed through or concentrate urine in his kidney collecting ducts. Polyuria (the chronic passage of large volumes of urine) and polydipsia (chronic, excessive thirst) are the primary symptoms of NDI. However, this disorder can manifest in the first week of life and then the symptoms are more alarming: constipation, fever, failure to thrive, vomiting, irritability and high blood sodium levels. If NDI goes undiagnosed and untreated, the resulting bouts of severe dehydration could lead to physical and mental retardation, and even death.

In 1969, Bode and Crawford proposed that most North American NDI patients were descendants of a common ancestral line, a group of Ulster Scots who arrived in Canada in 1761 aboard the ship, Hopewell. More recently, the association between mutations in the vasopressin-2 receptor (V2R) gene and NDI have been established. Holtzman, et al., analyzed the V2R gene mutations of one family lineage directly connected to the original Ulster Scot clan. The researchers found a distinct V2R mutation. This mutation involved a change in one of the nucleotide bases in the genetic sequence from a guanine to an adenine. This replacement results in a signal telling the mutated V2R gene to stop producing its V2R instead of telling it to produce a tryptophan amino acid. This caused the gene to produce a very premature truncation of the V2R, leaving it only 70 amino acids long instead of 371 amino acids long. This produced a V2R incapable of carrying out its required functions.

The researchers' data, combined with other research that shows that other V2R mutations have been found in descendants of the original Scots (as well as people from other ethnic origins) disproves Bode and Crawford's Hopewell hypothesis.