A totally lethal gene mutation, so the theory goes, would disappearfrom the population fairly soon, having killed off all the individualsharboring the mutant in their genome.Aberrant genes survive, in theory, because they confer an advantageon individuals who carry them that makes up for theirpathogenicity. A well-known example is sickle-cell anemia, causedby a mutant hemoglobin gene. It produces misshapen red bloodcells, which jam up the capillaries in the circulation.The sickling gene occurs mainly in people of West African ethnicorigin, where it protects carriers of the mutant against malaria. Ifonly one parent carries the sickling trait, he or she may pass it onharmlessly to the couple's offspring. But if both mother and fatherhave the mutation, their children are born with a one-in-four chanceof inheriting the life-threatening anemia, by being homozygous.Just as the sickle-cell gene predominates in black people (about 9percent of African-Americans carry it), so the mutant gene forcystic fibrosis (CF) is the most common, fatal, homozygousrecessive disorder of the Caucasian population.Now it turns out that CF has persisted down through the agesbecause it protects against cholera, a worldwide scourge throughouthuman history.How CF Works Against CholeraThis week's issue of Science (Oct. 7) tells the story, titled "CysticFibrosis Heterozygote Resistance to Cholera Toxin in the CysticFibrosis Mouse Model."The mutated gene product in CF is called the cystic fibrosistransmembrane conductance regulator (CFTR). This protein reducesthe flow of chloride ions (Cl-) across the membranes of manyepithelial tissues, notably those of the intestinal tract. Thus, manyinfants born with the mutant gene from both parents die quickly ofmeconium ileus, an obstruction of their small bowel.Children who survive this neonatal threat to life have usually diedyoung of blockages to pancreas, airways and other organs by thickmucus deposits. In recent years, improved medical care hassomewhat lengthened CF life expectancy.Cholera, on the other hand, kills by opening cell membranes to theuncontrolled discharge of water and its dissolved electrolytes. Thisefflux swiftly and fatally dehydrates its victims. (Two-thirds of thebody consists of water.) In this lethal secretory diarrhea, as in CF,the chloride-channel is implicated.As the principal author of the Science paper, Sherif Gabriel, anelectrophysiologist at the University of North Carolina, points out:"These two diseases are connected by the cAMP-regulated, Cl-channel CFTR." Gabriel noted that cAMP, cyclic adenosinemonophosphate, is ubiquitous in intestinal epithelium, where itregulates chloride-ion (Cl-) channels and fluid secretion that ensues."This chloride permeability," he wrote, "is mediated entirelythrough CFTR."The long-held hypothesis that CF endows its carriers with aselective advantage against cholera (as sickle cells do againstmalaria) has remained a hypothesis, Gabriel told BioWorld Today,for lack of an animal model to test it. His co-authors created such asurrogate in mice by successively cross-breeding normal mice withrodents in which they had knocked out the CFTR gene. Eventually,they had three model strains:u knockout animals lacking the mutant gene entirely _ CFTR-/-,u heterozygotes carrying only one mutant gene, _ CFTR+/-, andu homozygous mice, i.e., with genes mutated in both chromosomalarms _ CFTR+/+. (The CFTR gene resides on the long arm ofhuman chromosome 7.)First, Gabriel's group administered 10 micrograms of cholera toxinto normal homozygotes. Six hours later, the animals' intestineswere full of water. In cystic fibrosis homozygotes, the same choleratoxin dose produced no fluid outpouring whatever."Intestinal fluid secretion," the Science paper reported, "was highestin the CFTR+/+ mice, intermediate in the CFTR+/- mice, andlowest in the CFTR-/- mice."Gabriel suggests that "a plausible explanation of our results is thatfluid and Cl- secretion are proportional to the amount of CFTRprotein expressed in the intestinal epithelium."Hypothesis Is ProvenThe fact that one in 20 Caucasians harbors one copy of the mutantgene," Gabriel said, which is "higher than expected, supports thehypothesis that this trait protects its carriers against cholera."He cited a historical study, which calculated that "a mere twopercent increase in the number of CFTR carriers some 23 humangenerations ago, when cholera ravaged the population of medievalEurope, would cause the carrier frequency we see today,specifically because of the cAMP and CFTR connections betweenthe two diseases."Beyond at last bolstering the hypothesis, Gabriel sees clinicalutility in the CF-cholera connection. "It's of clinical interest to thesecretory diarrhea of cholera, which remains one of the leadingcauses of infant mortality around the world." He added, "That'scertainly one of the main aspects we'll be looking at. If we couldpotentially utilize some of the agents we know of that inhibit CFTR,we have a chance at pharmacological intervention against secretorydiarrhea."He concluded, "I guess the biotechnology field is probably the bestplace to go with it." n
-- David N. Leff Science Editor
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