Detection of Skewed X-Inactivation in Two Female Carriers of Vasopressin Type 2 Receptor Gene Mutation
|Title:||Detection of Skewed X-Inactivation in Two Female Carriers of Vasopressin Type 2 Receptor Gene Mutation|
|Authors:||Nomura, Yoko; Onigata, Kazumichi; Nagashima, Tomohisa; Yutani, Shigenori; Mochizuki, Hiroshi; Nagashima, K.; Morikawa, Akihiro|
|Publisher:||Journal of Clinical Endocrinology and Metabolism|
|Date Published:||October 01, 1997|
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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)
This principle applies to inheritance of genetic disorders. There are two alleles (forming one gene pair) responsible for the manufacture of a protein. If the dominant allele is mutated, then the disorder will be expressed. If the mutated allele is recessive, then the disorder will not be expressed unless both alleles carry the same mutation.
If a defective gene is located on a sex chromosome (nearly always the X, as opposed to the Y, chromosome) then the resultant disorder is called a sex-linked disorder. If the defective gene or gene pair is located on any of the other 22 pair of chromosomes, the resultant disorder is called an autosomal disorder. Most sex-linked disorders are called X-linked recessive disorders. They are the result of a mutated gene carried on the X chromosome. X-linked recessive disorders primarily affect males because males have only one X chromosome which they inherit from their mother (females have two X chromosomes) so there is no paired allele to potentially dominate it.
Most cases of congenital nephrogenic diabetes insipidus (CNDI) are transmitted in an X-linked recessive manner. The defective gene that is thought to cause it is located on the X chromosome. As in all X-linked recessive disorders, the mutated gene for the disorder is carried by the females, who are generally not affected by it (i.e., they seldom express CNDI symptoms, but their sons may).
However, females sometimes do express the symptoms of CNDI. Nomura, et al., examined an extended family where not only three males, but two out of the three females who carried the mutated gene expressed different degrees of symptoms of CNDI. All three women were heterozygous for a vasopressin-2 receptor (V2R) mutation (which can cause CNDI), which means one of their V2R alleles was normal and one was mutant. Female carriers of CNDI all have one normal and one mutant allele of the V2R gene, yet most do not express NDI symptoms. Why, then, did two of these females?
The grandmother displayed severe CNDI symptoms. The mother displayed mild symptoms. The daughter of the grandmother's sister displayed no symptoms. There could be several explanations as to why the grandmother and her daughter displayed symptoms:
- Both of their alleles could have carried the V2R gene mutation.
- Another gene that, if mutated, can be responsible for symptoms of NDI, the aquaporin-2 (AQP2) gene, could have been mutated.
- There could have been a defect in the chain of events that need to happen between the V2R and the AQP2.
- The mutant V2R gene could have had a dominant, rather than recessive, effect.
- A process known as X-inactivation could have occurred. In X-inactivation, all of the X chromosomes of the cells in excess of one are inactivated on a random basis. A variation of the X-inactivation process is called skewed X-inactivation. The X-inactivation, instead of being random, is more specific to the normal alleles, in this case the normal V2R allele.
The authors concluded that the cause in this case was X-skewed inactivation. Females with the same heterozygous mutation of the V2R gene may display symptoms of CNDI in varying degrees of intensity. The authors' tests showed that the grandmother, who had severe CNDI symptoms, had extremely skewed X-inactivation. The mother, who had mild CNDI symptoms, had less skewed inactivation. And the daughter of the grandmother's sister, who had no symptoms, had random X-inactivation. These findings suggest that the degree of non-random (skewed) X-inactivation correlates with the degree of intensity of expression of CNDI symptoms.