In the year 1761, the good ship Hopewell reached Nova Scotia, with anumber of Scottish people from Ulster on its passenger list. Theirdescendants live in that Canadian province to this day, and many ofthem suffer from a rare disease handed down by those 18th-centuryfounder ancestors.It's called familial nephrogenic diabetes inspidus (FNDI), not to beconfused with diabetes mellitus (lack of insulin) or central diabetesinsipidus (lack of the hormone, arginine-vasopressin).The Greeks had a word for diabetes, "diabainein," meaning to walk orstand with legs apart, as when urinating. In both diseases, mellitus andinspidus, excessive urination is a hallmark, but far more so in theinsipidus forms -- central and nephrogenic.Patients with either type of insipidus have a round-the-clock ragingthirst (polydipsia), and a matching urge to "go" (polyuria). They spendtheir waking and sleeping hours passing water at the rate of gallons aday, and gulping water to keep up with the urinary dehydration. Theaverage healthy adult needs to down two to three liters of water a day.This fluid intake is balanced by fluid outgo, via perspiration andurination.The hormone that controls the urinary equilibrium is arginine-vasopressin, a.k.a. the antidiuretic hormone (ADH). Vasopressinmanages the body's water content by constricting blood vessels, andsignaling the kidneys to make and excrete urine. That message reachesthe kidneys by way of ADH receptors on blood vessels and the renaltubules.When that hormone's receptor is mutated, the kidney never gets theanti-diuretic command to absorb water. Therefore, it constantlyreleases a thin, pale liquid almost the consistency of pure water _ hencethe term "insipidus."Missing Hormone, Defective ReceptorFamilial nephrogenic diabetes insipidus is a mercifully rare affliction,until very recently blamed on a single mutant gene in a region of the Xchromosome's long arm where the vasopressin receptor gene alsomaps. Because males have only one X, a sizable majority of FNDIpatients are male.Neurogenic, or central diabetes inspidus (CDI) arises from lack ormutation of the ADH hormone itself, which is made in the brain'sposterior pituitary gland. CDI may arise from gene mutation or trauma;its clinical symptoms are identical to those of FNDI sufferers, but itsincidence, according to National Institutes of Health estimates, runsaround one in 25,000 people.The CDI patients can be treated with replacement hormone analogs,but the nephrogenic ones have no way to revive the kidney receptorsthat put that ADH to work. Their life sentence of polydipsia andpolyuria is complicated in neonates born with the disease.Because of their enormous urinary outflow, these infants are known inthe pediatric wards as "water-babies." For them, diabetes inspidus canbe life-threatening. "A child too young to articulate its need to drinkcan go into convulsion and coma," said endocrinologist Eitan Friedmanof M.D. Anderson Cancer Center in Houston, "may have brain damage,learning disabilities and hydronephrosis." This is a swelling of thekidneys' water-collecting system.Friedman told BioWorld Today that he estimates the number ofnephrogenic diabetes insipidus patients at "less than 100 familiesthroughout the world." He cites, "as a limited sampling," four knownfamilies among Sweden's 8 million people, three in Israel's 5 million,two in Brazil's population of 150 million, and nine U.S. familiesreported in recent research papers.Friedman is the lead author of a paper in the current Proceedings of theNational Academy of Sciences (PNAS) titled: "Nephrogenic diabetesinsipidus: An X-chromosome-linked dominant inheritance pattern witha vasopressin type 2 receptor gene that is structurally normal."The vasopressin type 2 receptor gene (V2R) is variously mutated inaffected individuals, so is suspected of causing the disease, Friedmanexplained, by X-linked recessive inheritance. Using polymerase chainreaction, electrophoresis and direct DNA sequencing, he and his co-authors in Sweden and Brazil examined the gene in four unrelatedextended families.The largest of these, in Brazil, spanned five generations, 21 of whose78 members (including the great-grandfather) had or have FNDI. Thiskindred displayed an X-linked dominant rather than recessive mode ofgenetic transmission, and its affected individuals, strangely, had nomutated V2R genes. Moreover, more than half of them were females.Hunting Down The Third Gene"These new indications," Friedman concluded, "raised the possibilitythat a gene other than V2R caused their disease. Our impetus," heexplained, "was to look for mutations within this gene, and try to find ifit, or a different type of inheritance, was responsible for FNDI." Hediscovered "A very nice polymorphism marker within the V2R codingregion of the chromosome -- which is begging for a lot of markers. Tome," he added, "it just provides a very rapid, non-radioactive andaccurate method of screening for mutations in this disease."Meanwhile, a report from the Netherlands announced a gene onchromosome 12, which encodes a water-channel. "In one Dutchfamily," Friedman said, "where the inheritance was not X-linked, butautosomal recessive, they found mutations within this gene." His ownresearch "finds that there is potentially a third gene that has to do withwater-handling in the kidney, and may be responsible for FNDI in oneof the families we analyzed."He speculates that, "this third, putative, gene is probably located on theX chromosome, close to but not identical with the V2R gene. Linkageanalysis found markers suggesting that this second gene lies farther outon chromosome X."The therapeutic aspect of our work," he concludes, "is to find a way ofcorrecting the particular genetic defect, which varies from family tofamily, by gene therapy." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.