Three-point Linkage Analysis using Multiple DNA Polymorphic Markers in Families with X-linked Nephrogenic Diabetes Insipidus

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Title: Three-point Linkage Analysis using Multiple DNA Polymorphic Markers in Families with X-linked Nephrogenic Diabetes Insipidus
Authors: Monnens, Leo A.H.; Knoers, Nine; van Oost, Bernard A.; van der Heyden, H.; Ropers, Hilger H.; Willems, J.
Publisher: Genomics
Date Published: April 01, 1989
Reference Number: 257
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The gene for X-linked nephrogenic diabetes insipidus (NDI), a disorder which, if untreated, causes severe dehydration, mental retardation, and possibly death in affected males, has been mapped recently to the Xq28 band through demonstration of linkage to the DX552 locus and other DNA markers (N. Knoers et al., 1987, Cytogenet. Cell Genet. 46:640; M. Kambouris et al., 1987, Cytogenet. Cell Genet. 46:636). Linkage studies in 11 families with NDI have enabled us to map the NDI gene between closely linked flanking markers in the Xq28 region and to obtain the following gene order: centromere-F9-DXS98-F8/CBD,CBP-DXS52/NDI-DXS134- telomere. These results have implications for presymptomatic and prenatal diagnosis of NDI and should also improve the prospects for identifying the fundamental gene defect underlying this disorder.

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)

A genetic marker is a segment of DNA, such as a gene that can be identified and whose chromosomal location is known. Researchers use genetic markers to help them locate the chromosomal location of other genes. Finding the location of a gene enables researchers to clone and analyze it to see what physiological role it plays when healthy, and what defects it may cause when mutated. Researchers need to use markers because the chromosomal scale is so small that the location of genes cannot be directly perceived, but only inferred through expression analysis.

The gene that, when mutated, causes X-linked nephrogenic diabetes insipidus (NDI) is called the NDI gene because researchers do not yet know what gene it is. The NDI gene has been mapped to the Xq28 region of the X chromosome, because it was shown to be linked to the DNA marker DX552, which is known to exist in Xq28 region. Knoers, et al., set out to define the position of the NDI gene more precisely by using several genetic markers in their analysis of 11 families with, among them, 20 males affected with inherited NDI. The researchers found that the NDI gene is located in the close vicinity of markers DXS52, DX533 and DXS15. These markers are themselves tightly linked in the Xq28 region of the X chromosome.

The authors' analysis also allowed them to discover the following gene order in the Xq28 region of the X chromosome: centromere-F9-DXS98-F8/CBD, CBP-DXS52/NDI-DXS134-telomere. The centromere is the constricted part of the X chromosome, the part that crimps in like a tight belt. The telomere is what researchers call the extremities of the chromosome, i.e. either end of the chromosome. If you imagine the X chromosome standing vertically, like a narrow rectangle, the centromere is about one third of the way down from the top, and the Xq28 region is at the very base. Thus, the markers F9-DXS98-F8, though still in the Xq28 region, are the ones closer to the centromere and are at the top of the order.

The gene order the authors discovered has the NDI gene between the CBD, CBP-DXS52 gene order and the DXS134 gene at the base telomere. These refinements of location -- showing the gene order in which the NDI gene occurs in the Xq28 region, finding three markers to which the NDI gene is closely linked, and finding the markers which flank the NDI gene -F8 as well as CBD, CBP on one side, and DXS134 on the other, -- should greatly increase the reliability of determining if a female carries the NDI gene and the reliability of early prenatal diagnosis. It should also improve the prospects for cloning the NDI gene.