When pledging allegiance to the flag, Americans place theirright hand over their heart. But one in 10,000 Americans maynot have their hearts in the right place -- anatomically, that is,not patriotically.

This minority, born with hearts on the right side of their body,suffer from an unusual genetic anomaly, Kartagener'ssyndrome, in which not only the heart, but the liver, stomachand other unpaired organs are flip-flopped left to right. Thismirror-image, visceral inversion, known as situs inversus, isassociated with chronic sinus and bronchial infection, as well ascardiovascular and pulmonary disorders.

Medical geneticists have known that situs inversus is inheritedas an autosomal recessive syndrome ever since 1935, whenKartagener described it in the Swiss Medical Weekly SchweizMed. Wochenschr. But the molecular mechanism of thisaberrant vertebral polarity remained a mystery untilresearchers at Baylor College of Medicine in Houston stumbledon a key clue to its genetic cause late last year.

Their report, by Paul A Overbeek and colleagues in today'sScience, is titled "Reversal of Left-Right Asymmetry: A SitusInversus Mutation."

The Texans weren't looking for any such prenatal-developmental phenomenon. Rather, they had set out to createa transgenic, pigmented colony of albino mice by microinjectingtyrosinase minigenes into one-cell-stage embryos. Holding anewborn transgenic pup up to the light, they could see throughits translucent skin a stomachful of milk pointed the wrongway. Dissection revealed that heart and other vitelline organsalso faced right instead of left. None of these organ-reversed,homozygous mice lived longer than seven days. The Baylorteam replenishes their population by breeding theheterozygous albino mice, whose transgenic members arereadily spotted by their pigmented eyes.

Overbeek surmises that an "insertional event" -- a mechanicalbreak in the genome -- occasioned by the gene transfer, ratherthan its expression, caused the situs inversus recessivemutation, which inactivated the polarity gene. DNA probesflanking the transgenic insertion site were cloned and mappedto a gene, locus unknown, on mouse chromosome 4.

The researchers dubbed this the inv gene locus, inv standingfor "inversion of embryonic turning." Breeding experimentsconfirmed that 100 percent of homozygous animals had themurine equivalent of Kartagener's syndrome.

Since submitting the paper to Science last December, Overbeektold BioWorld, "most of the work we've done is to try to makeprogress toward isolating the gene that was inactivated at thesite of the mutation." He said he hopes that "when we find themouse gene, hybridization studies will show that it is also ahuman gene."

It's a long leap in the dark from mouse to human, so the Baylorscientists are making no claim that their serendipitousdiscovery that a gene mutation causes the visceral inversion inMus musculus can be extrapolated to Homo Sapiens. Butbiologist Lewis Wolpert of University College, London, said, "It'sa remarkable finding. We know a lot about anterior-posteriorpositioning in vertebrates, yet we have so little understandingof left-right polarity."

Quoted in a Science editorial to the Baylor paper, Wolpertadded, "It could hold the key to understanding how suchproblems as cardiac defects are associated with reversal ofinternal organs."

William Layton, professor emeritus of anatomy at DartmouthMedical School, told BioWorld that the inversion "is associatedwith a tenfold increase in the incidence of heart malformations,from eight in 1,000 to eight in 100." He said that "Overbeek'sdata look good," and "in some ways could serve as a model ofthat kind of cardiac malformation."

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.