X-Linked Nephrogenic Diabetes Insipidus Mutations in North America and the Hopewell Hypothesis
| Title: | X-Linked Nephrogenic Diabetes Insipidus Mutations in North America and the Hopewell Hypothesis |
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| Authors: | Bichet, Daniel G.; Arthus, Marie-Francoise; Lonergan, Michele; Hendy, PhD, Geoffrey N.; Paradis, Ann Josee; Fujiwara, T. Mary; Morgan, Kenneth; Gregory, Martin C.; Rosenthal, Walter; Didwania, Arati |
| Publisher: | Journal of Clinical Investigation |
| Date Published: | September 01, 1993 |
| Reference Number: | 123 |
In X-linked nephrogenic diabetes insipidus (NDI) the urine of male patients is not concentrated after the administration of the antidiuretic hormone arginine-vasopressin. This disease is due to mutations in the V2 receptor gene that maps to chromosome region Xq28. In 1969, Bode and Crawford suggested that most NDI patients in North America shared common ancestors of Ulster Scot immigrants who arrived in Halifax in 1761 on the ship Hopewell. A link between this family and a large Utah kindred was also suggested. DNA was obtained from 17 affected male patients from the "Hopewell" kindred and from four additional families from Nova Scotia and New Brunswick who shared the same Xq28 NDI haplotype. The Utah kindred and two familes (Q2, Q3) from Quebec were also studied. The "Hopewell" mutation, W71X, is a single base substitution (G-->A) that changes codon 71 from TGG (tryptophan) to TGA (stop). The W71X mutation was found in affected members of the Hopewell and of the four satellite families. The W71X mutation is the cause of X-linked NDI for the largest number of related male patients living in North America. Other families (Utah, Q2 and Q3) that are historically and ethnically unrelated bear other mutations in the V2 receptor gene.
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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)
In 1969, Bode and Crawford formed the Hopewell hypothesis. They hypothesized that most NDI patients in North America shared common ancestors of Ulster Scot immigrants who arrived in Canada in 1761 on the ship, Hopewell. More recent advances in genetics have allowed Bichet, et al., to perform direct mutational analysis on 17 NDI patients from the Hopewell lineage. They compared the results with their mutation analysis of the V2R genes of one family lineage in Utah where NDI was prominent, and two NDI families from Quebec. They found the V2R gene mutations from the Hopewell lineage was different from the other NDI families studied. And each of the other families had different V2R gene mutations amongst themselves. This shows that in each of these families, NDI had an independent origin.
Most of the V2R, called the transmembrane domains 1 - 7, lies folded in seven clumps within the cell membrane, that thin strip of tissue that encircles the cell, separating the inside of it from the outside. Part of the V2R snakes outside the cell forming three curves called extracellular loops 1 - 3. Part of it snakes inside the cell forming three curves called intracellular loops 1 - 3. One end of the V2R, called the amino-terminus, lies outside the cell with the extracellular loops. The other end, called the carboxy-terminus, lies inside the cell with the intracellular loops. (Please refer to an illustration of V2R.)
To date, 16 mutations of the V2R gene have been reported. The majority of these mutations are reflected within the third extracellular loop, the third transmembrane domain, or the third intracellular loop of their respective V2Rs. These areas have been shown to be important for various essential V2R functions such as binding with AVP and coupling with the G-protein. However, other V2R gene mutations (such as the one causing NDI in the Hopewell lineage) are reflected in other areas of the V2R.
Researchers are currently studying the structure-function relationship in V2Rs, analyzing how each V2R gene mutation affects the structure of the V2Rs it synthesizes, and how that structural alteration interferes with the set of functions the V2R must perform.