2004 Global Researcher Conference Proceeding
April 09 - 11, 2004
| Conference: | 2004 Global Researcher Conference |
|---|---|
| Title: | Rediscovery of Swedish Kindred with X-linked 'Vasopressin-Responsive' Diabetes Insipidus: Validation and Explanation of the Unusual Clinical Phenotype |
| Authors: | Robertson, Gary; Kopp, M.D., Peter; Rittig, Soren; Johannsson, J. |
| Institutions: | Northwestern University Medical School, Northwestern University, Skejby University Hospital, Sahlgrenska University Hospital |
In 1945, Dr. Hans Forssman reported three kindreds with diabetes insipidus (DI) inherited in an X-linked recessive mode (xrDI). One kindred had no antidiuretic response to 1 IU of injected Pituitrin (vasopressin, VP) indicating that their DI was caused by resistance to VP (nephrogenic xrDI). However, the other two kindreds with xrDI responded to the test dose of Pituitrin, suggesting that their DI was caused by a VP deficiency (pituitary xrDI). He also surmised that the larger kindred, which comprised 5 families (A-G) and nearly 5,000 members going back to a foremother born in 1712, was related to the smaller kindred of 1 family (H) since they came from adjacent villages.
An alternative explanation for VP responsive xrDI was suggested in 1981 by discovery of partial nephrogenic xrDI. This phenotype, which is due to a shift to the right in the relation of urine osmolarity to plasma VP, also responds well to large doses of VP or its analogue dDAVP and occurs with several mutations of the gene encoding the VP receptor, AVPR2 (D85N, G201D, P322S, S329R). However, the issue was re-opened in 1996 by the discovery of an American kindred with documented xr Pituitary DI that responded well to treatment with normal doses of dDAVP and linked to markers in Xq28 but had normal AVPR2 and VP-precursor genes.
To resolve this uncertainty about the cause of the VP responsive xrDI in Forssman’s patients, we undertook a search for their descendants. Though impeded by precautions to conceal their identity, we eventually obtained his personal thesis book in which he had handwritten the names of the original patients. With this information, extensive genealogical research in various Swedish registries and assistance from the patients themselves, we succeeded in identifying 10 affected males and 20 female carriers from all surviving families of both kindreds. Testing of affected males from families B, E, G and H show that all of them have the same novel mutation of the AVPR2 gene (310C>T, R104C) in association with moderate to severe DI, normal to elevated plasma VP and a subnormal rise in urine osmolarity in response to VP infusion. We conclude that the patients from both of Forssman’s kindreds had partial nephrogenic DI due to the same mutation of the AVPR2 gene and, as he surmised, probably are related.
A kindred is a group of people related by blood or marriage. Medical researchers often study generations of the same kindred to discover the means by which diseases are inherited. In 1945, Dr. Hans Forssman reported three kindreds with X-linked recessive Diabetes Insipidus (DI). X-linked recessive means the disease is due to mutation of a gene on the X chromosome and affects only the males who inherit it. It does not affect female carriers because, unlike males, they have two X chromosomes and only one of them carries the normal gene which is enough to prevent the DI. Forssman concluded that one of his kindreds had NDI which is caused by a resistance to the antidiuretic hormone, arginine vasopressin (AVP) and is usually inherited in an X-linked mode. However, the DI in the other two kindreds responded to high doses of AVP and was thought to be caused by a deficiency in AVP. This is called pituitary DI and is rarely inherited in an X-linked recessive way.
In 1981, research suggested that the kindred with pituitary NDI might have actually had partial NDI instead. Robertson, et al., researched the descendents of Forssman’s patients, finding ten affected males and 20 female carriers from surviving families of both kindreds. They found that all of them had the same mutation in their arginine vasopressin receptor 2 (AVPR2) gene. In addition, the affected males all had moderate to severe DI, had normal to elevated amounts of AVP in their blood, and responded to very high but not normal amounts AVP. This evidence proved that the two kindreds that were originally thought to have pituitary DI had instead partial NDI.