Proposed Cause of Marked Vasopressin Resistance in a Female with an X-Linked Recessive V2 Receptor Abnormality

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Title: Proposed Cause of Marked Vasopressin Resistance in a Female with an X-Linked Recessive V2 Receptor Abnormality
Authors: Moses, Arnold M.; Sangani, Geeta; Miller, Jonathan L.
Publisher: Journal of Clinical Endocrinology and Metabolism
Date Published: April 01, 1995
Reference Number: 71
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Almost all cases of congenital nephrogenic diabetes insipidus (NDI) are transmitted in an X-linked recessive manner by an asymptomatic carrier female to her affected son. Severe symptomatic NDI has not previously been reported in a female with X-linked recessive NDI. Each of the three members of this family has an abnormal V2 receptor gene, which results in truncation of the V2 receptor beginning at arginine-337. This prematurely terminates the receptor at the carboxy-terminal tail and very likely disrupts receptor function. The son has an abnormal V2 receptor gene on his X-chromosome, whereas the mother and daughter have one normal and one abnormal gene for the V2 receptor. The infusion of desmopressin into the mother and son reveals a total lack of antidiuretic response, whereas the daughter increases urinary osmolality normally. The plasma factor VIII concentration after the infusion of desmopressin in the son does not rise, whereas the mother and daughter have half of the normal factor VIII response, similar to asymptomatic female carriers of NDI. These responses to desmopressin in daughrter and son are those of a typical carrier female and male affected with NDI. In contrast, the mother acts as an NDI patient when the urine concentration is measured, but acts as a carrier in terms of the factor VIII response to desmopressin. We postulate that the renal tubular cells of the mother demonstrate extreme lyonization of X-chromosome inactivation, whereas in the tissue that subserves the hematological response to desmopressin, X-chromosome inactivation followed a more typically random distribution.

The following article is presented with the permission of the publisher for educational use within the NDI community. No part of this article may be reproduced in any way without permission in writing from the publisher.


Almost all cases of congenital nephrogenic diabetes insipidus (NDI) are transmitted in an X-linked recessive manner by an asymptomatic carrier female to her affected son. Severe symptomatic NDI has not previously been reported in a female with X-linked recessive NDI. Each of the three members of this family has an abnormal V2 receptor gene, which results in truncation of the V2 receptor beginning at arginine-337. This prematurely terminates the receptor at the carboxy-terminal tail and very likely disrupts receptor function. The son has an abnormal V2 receptor gene on his X-chromosome, whereas the mother and daughter have one normal and one abnormal gene for the V2 receptor. The infusion of desmopressin into the mother and son reveals a total lack of antidiuretic response, whereas the daughter increases urinary osmolality normally. The plasma factor VIII concentration after the infusion of desmopressin in the son does not rise, whereas the mother and daughter have half of the normal factor VIII response, similar to asymptomatic female carriers of NDI. These responses to desmopressin in daughter and son are those of a typical carrier female and male affected with NDI. In contrast, the mother acts as an NDI patient when the urine concentration is measured, but acts as a carrier in terms of the factor VIII response to desmopressin. We postulate that the renal tubular cells of the mother demonstrate extreme lyonization of X-chromosome inactivation, whereas in the tissue that subserves the hematological response to desmopressin, X-chromosome inactivation followed a more typically random distribution. (J Clin Endocrinol Metab 80: 1184-1186, 1995)

From the earliest reports on congenital vasopressin-resistant diabetes insipidus (NDI) in man, researchers have emphasized that the vast majority of cases occur in males and are transmitted in an X-linked recessive manner (1-3). Female carriers are usually asymptomatic, but may have mild impairment of urine-concentrating ability (1-3). To date, there are no documented reports of females with the X-linked recessive inheritance pattern of NDI having severe hypotonic polyuria. When females have been reported with severe symptomatic congenital NDI, there has been either no hereditary pattern of NDI (4, 5) or transmission that was X-linked dominant (6), autosomal recessive (7), or autosomal dominant (8).

For some years, the proposed cause of X-linked NDI was thought to be an abnormality of V2 (antidiuretic) receptor function per se (9, 10). The reason for this belief was that the V2 agonist desmopressin, which normally causes vasodilatory, coagulation, and fibrinolytic responses by activating extrarenal V2 receptors, does not have this effect in men with X-linked NDI (10, 11). Linkage studies have demonstrated that the gene responsible for X-linked recessive NDI is on the long arm of the X-chromosome in region Xq28 (12). The first reports of mutant V2 receptor genes with altered translational products in patients with X-linked NDI appeared in late 1992 (13-15), and many reports of different mutations of the V2 receptor have followed (16-20). Bichet (21) has recently summarized these reports.

We have for some time been aware of a mother and son with severe symptomatic congenital NDI, with a phenotypically normal daughter. In an effort to clarify the molecular basis of the defect in this family, Wenkert et al. (19) sequenced the appropriate leukocyte DNA from the three patients and demonstrated a change in CGA to the stop codon TGA, corresponding to a truncation of the intracellular carboxy-terminal tail of the V2 receptor at arginine-337. All three subjects have one abnormal V2 receptor gene. The mother and daughter have one normal V2 receptor gene and are, therefore, considered to be carriers. The same abnormality (truncation at arginine-337) has been reported by Knoers et al. (18). To gain insight into the reason why the mother and daughter are genotypically similar but phenotypically different, we infused the members of this family with desmopressin and measured their plasma factor VIII responses.

The results provide insight into the possible mechanism by which the mother in this family with X-linked recessive NDI may have developed marked vasopressin-resistant hypotonic polyuria.


Subjects and Methods


Experimental subjects

The age and sex of the three experimental subjects are indicated in Tables 1 and 2. The protocol was also conducted in nine normal females, ages 20-40 yr.

All subjects were admitted to our clinical research unit at 0800 h. They were permitted a light breakfast without any caffeine and allowed to drink water ad libitum during the study. An iv catheter was inserted, and they were recumbent for 1 h. Desmopressin was then infused iv in the amount of 0.4 ?g/kg BW over 15 min. Blood and urine specimens were obtained at the times indicated in Tables 1 and 2 for factor VIII coagulant activity, and urine volume and osmolality. Osmolality was determined by freezing point depression, using an Advanced Instruments Digimatic osmometer (Advanced Instruments, Needham, MA). Plasma factor VIII coagulant activity was measured by a modification of the partial thromboplastin time in a one-stage assay (22), using severely deficient factor VIII plasma as substrate. This protocol was approved by the Institutional Review Board for the Protection of Human Subjects, State University of New York (Syracuse, NY), and informed consent was obtained from each subject.

TABLE 1. Urinary osmolality before and after the infusion of 0.4 µg/kg BW desmopressin in normal subjects and three patients in a family with congenital nephrogenic diabetes insipidus.

Urinary osmolality (mmol/kg)

-2 to 0 h
0-2 h
2-4 h
4-6 h

Normal (9)
570 ± 275
776 ± 137
936 ± 137
1016 ± 112
NDI family
   Mother (32 yr)
91
103
99
94
   Daughter (8 yr)
689
772
990
1017
   Son (10 yr)
128
129
128
115

Normal data are the mean ± SD.



TABLE 2. Plasma factor VIII coagulant activity levels before and after the infusion of 0.4 µg/kg BW desmopressin in normal subjects and three patients in a family with congenital nephrogenic diabetes insipidus.

Plasma factor VIII coagulant activity (U/dL)

0 min
30 min
60 min
120 min

Normal (9)
96.7 ± 17.3
280.8 ± 70.1
332.2 ± 96.1
316.8 ± 60.7
NDI family
   Mother (32 yr)
120
180
215
230
   Daughter (8 yr)
100
168
188
232
   Son (10 yr)
118
97
130
124

Normal data are the mean ± SD.


Results


The infusion of desmopressin (0.4 µg/kg BW) into the mother and the son revealed a total lack of antidiuretic response, whereas the daughter concentrated her urine normally in response to the large infused dose of desmopressin (Table 1). The plasma factor VIII concentration after desmopressin infusion in the mother and daughter increased to half the normal response, whereas the son had no rise in plasma factor VIII concentration (Table 2).

Discussion


The leukocyte DNA from each of the three members of this family contains an abnormal gene for NDI in the Xq28 locus (the females also have a normal V2 receptor gene) (19). Knoers et al. (18) described the same abnormality. The abnormal base sequence is a nonsense mutation (CGA to TGA) which translates to a stop codon. This abnormality interrupts translation at arginine-337 (the normal receptor has 371 amino acids). This abnormality is presumed to disrupt normal receptor function (18, 19).

The severe hypotonic polyuria in the son and the normality of concentrating mechanism in the daughter are expected in members of families with X-linked recessive NDI. The mother, who is genetically identical to her daughter in studies using peripheral blood leukocytes, has severe NDI and, therefore, demonstrates an unexpected phenotype for a carrier female.

Carrier females in families with X-linked NDI characteristically have half the normal factor VIII response to desmopressin (23). In the present study, this half-normal response occurs in both mother and daughter, whereas the son has no factor VIIII response to desmopressin, as is typical of males with X-linked recessive NDI (23). It is conceivable that the mother has an additional, as yet unidentified, defect in her kidneys that impairs the antidiuretic action of vasopressin at the postreceptor level. However, a more likely possibility in our opinion is that these family members have a single mutation of the V2 receptor affecting at least two different tissues that subserve the physiological responses to desmopressin. We propose that in the case of the mother, renal tubular cells underwent the well characterized phenomenon of extreme lyonization of X-chromosome inactivation, which has recently been reviewed in patients with X-linked disease states (24-29). In contrast, in the still unidentified tissue that subserves the hematological response to desmopressin, X-chromosome inactivation would have followed a more typical random distribution. In contrast to the mother, the daughter would have had a typical random distribution of X-chromosome inactivation in both tissues.


Acknowledgments


The authors acknowledge the expert technical assistance of Susan Graham. They are also grateful for the expert assistance provided by the nursing staff of the Clinical Research Unit, University Hospital.


References



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2. Williams RH,Henry C. 1947 Nephrogenic diabetes insipidus: transmitted by females and appearing during infancy in males. Ann Intern Med. 27:84-95.

3. Bode HH, Crawford JD. 1969 Nephrogenic diabetes insipidus in North America-the Hopewell hypothesis. N Engl J Med. 280:750-754.

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7. Langley JM, Balfe JW, Selander T, Ray PN, Clarke JTR. 1991 Autosomal recessive inheritance of vasopressin-resistant diabetes insipidus. Am J Med Genet. 38:90-94.

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Departments of Medicine and Pathology, State University of New York Health Science Center (A.M.M., G.S., J.L.M.)

April 1995

Address requests for reprints to Dr. Arnold M. Moses, Departments of Medicine and Pathology, State University of New York Health Science Center, 750 East Adams Street, Syracuse, New York 13210.

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 the vast majority of cases, congenital nephrogenic diabetes insipidus (NDI) is transmitted in an X-linked recessive manner from a mother to her son. The mother does not express the symptoms of NDI, but her son does. The female carries the mutant gene that causes NDI, but does not express its symptoms, whereas her male offspring, if he gets the mutated gene, will express the symptoms of NDI: chronic, excessive thirst and chronic, excessive urination. These symptoms appear because the kidneys cannot concentrate urine when signaled to do so by the antidiuretic hormone, vasopressin (VP). The mutations that impair or completely disallow the proper response to VP is a mutation of the V2 receptor gene located on the X chromosome. The V2 receptor is what VP is supposed to bind with to transmit its message to the kidneys, but when the V2 receptor is defective, VP cannot bind with it and the urine concentration process fails to occur.

As mentioned, the female carriers of NDI usually have no symptoms of the disease, though they may have some mild impairment of urine concentrating ability. Moses, et al., however, were aware of a mother and son, both of whom expressed the symptoms of NDI. Further, the mother had a daughter who also carried a mutated V2 receptor gene, but did not express any symptoms.

To understand the molecular basis of the defect, Moses, et al., analyzed DNA samples from the three subjects. They found the three subjects all had the same mutation in the V2 receptor gene: a nonsense mutation that resulted in the gene stopping prematurely and causing the V2 receptor to miss part of its tail. All three patients had one abnormal V2 receptor gene; the mother and daughter also had one normal V2 receptor gene. (The V2 receptor gene is located on the X chromosome; females have two X chromosomes, while males have one.)

To understand why the mother expressed symptoms and the daughter did not, the researchers administered synthetic VP (desmopressin) to the subjects and a control group of nine normal females. The researchers measured their response to the desmopressin in terms of urine concentration and concentration of plasma factor VIII. (Plasma factor VIII is a substance in the blood that is essential for the clotting process, and therefore important for the ability to stop bleeding. This factor is also transferred as a sex-linked [on the X chromosome] recessive trait).

The typical X-linked NDI patient will not respond to desmopressin because his V2 receptor is non-functional. In this case, neither the mother nor the son's urine concentration rose in response to desmopressin, but the daughter's did. However, both mother and daughter's plasma factor VIII concentration increased to half the normal response after the infusion of desmopressin, whereas the son showed no rise in his plasma factor VIII concentration.

The responses of the son and daughter to desmopressin are typical of families with X-linked recessive NDI. The response of the mother to desmopressin as measured by plasma factor VIII concentration is typical. Her response as measured by urine concentration is atypical. The authors hypothesize that these family members have a single mutation of the V2 receptor that affects at least two different tissues that promote physiological responses to desmopressin. They theorize that the mother's cells that help comprise the little tubes that filter bodily fluids in the kidneys had an atypical random X-chromosome inactivation. This inactivation pattern inactivated the mother's X-chromosomes that would have allowed her to have a typical response to desmopressin. Whereas in the still unidentified tissue that promotes the blood's response to desmopressin, the X chromosomes had a more typical pattern of random X chromosome inactivation. Thus the substances needed to respond to Plasma VIII were available. In contrast, the daughter would have had a typical random distribution of X-chromosome inactivation in both tissues.