X-linked Nephrogenic Diabetes Insipidus: from the Ship Hopewell to RFLP Studies
| Title: | X-linked Nephrogenic Diabetes Insipidus: from the Ship Hopewell to RFLP Studies |
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| Authors: | Bichet, Daniel G.; Hendy, PhD, Geoffrey N.; Lonergan, Michele; Arthus, Marie-Francoise; Ligier, MD, Sophie; Pausova, Zdenka; Kluge, Hans; Zingg, Hans H.; Saenger, MD, Paul; Oppenheimer, MD, Ellen; Hirsch, David J.; Gilgenkrantz, Simone; Salles, Jean-Pierre; Oberle, Isabelle; Mandel, Jean-Louis; Gregory, Martin C.; Fujiwara, T. Mary; Morgan, Kenneth; Scriver, Charles R. |
| Publisher: | American Journal of Human Genetics |
| Date Published: | November 01, 1992 |
| Reference Number: | 296 |
Nephrogenic diabetes insipidus (NDI; designated 304800 in Mendelian Inheritance in Man) is an X-linked disorder with abnormal renal and extrarenal V2 vasopressin receptor responses. The mutant gene has been mapped to Xq28 by analysis of RFLPs, and tight linkage between DXS52 and NDI has been reported. In 1969, Bode and Crawford proposed, under the term "the Hopewell hypothesis," that most cases in North America could be traced to descendants of Ulster Scots who arrived in Nova Scotia in 1761 on the ship Hopewell. They also suggested a link between this family and a large Mormon pedigree. DNA samples obtained from 13 independent affected families, including 42 members of the Hopewell and Mormon pedigrees, were analyzed with probes in the Xq28 region. Genealogical reconstructions were performed. Linkage between NDI and DXS304 (probe U6:2.spl), DXS305 (St35-691), DXS52 (St14-1), DXS15 (DX13), and F8C (F814) showed no recombination in 12 families, with a maximum lod score of 13.5 for DXS52. A recombinant between NDI and DXS304, DXS305, was identified in one family. The haplotype segregating with the disease in the Hopewell pedigree was not shared by other North American families. PCR analysis of the St14 VNTR allowed the distinction of two alleles that were not distinguishable by Southern analysis. Carrier status was predicted in 24 of 26 at-risk females. The Hopewell hypothesis cannot explain the origin of NDI in many of the North American families, since they have no apparent relationship with the Hopewell early settlers, either by haplotype or by genealogical analysis. We confirm the locus homogeneity of the disease by linkage analysis in ethnically diverse families. PCR analysis of the DXS52 VNTR in NDI families is very useful for carrier testing and presymptomatic diagnosis, which can prevent the first manifestations of dehydration.
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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 this study Bichet, et al., studied a total of 13 families who had some of their family members affected with NDI. The families were from diverse ethnic backgrounds (five French Canadian, one African American, one Puerto Rican, one Iranian, two French and three English). All together the authors studied 38 males affected with NDI, 18 nonaffected males, 30 females who carried the NDI gene and 26 females who could possibly carry the NDI gene.
Bichet, et al., had several research objectives:
- They wanted to test the assumption that the chromosomal location of the altered gene responsible for NDI was the same in all the affected families.
- They wanted to test the hypothesis put forward by Bode and Crawford that NDI patients in eastern North America shared a common Ulster Scot ancestory. They reasoned that if recombination in the Xq28 region is rare and if the mutant NDI gene in the Ulster Scot family tree is identical, then the haplotypes - sets of closely linked genes - of the Xq28 loci segregating with the disease should be identical in the NDI families in the study.
- They wanted to determine whether DNA analysis could identify those people in the families who were heterozygotes in regard to the NDI gene. That is, if they could identify those who carried one normal NDI gene and one mutated NDI gene.
In all the families tested, the NDI gene was always in the Xq28 region of the X chromosome, thus showing the chromosomal location was the same in all families. However, geneological haplotype analysis showed that Bode and Crawford's Ulster Scot family was not the source of all the cases of NDI in Northeastern America. Different haplotypes segregating with the diseases were observed among independent families, suggesting independent origins of NDI mutations. Through DNA analysis, the authors were able to infer those females who carried the NDI gene in 24 out of 26 cases. The authors propose that suspect male fetuses could be checked for NDI status through DNA analysis. Or they could have their status determined immediately after birth.