It took 10 years for neurogeneticist Thomas Bird and hisco-workers to map the missing gene for early-onsetAlzheimer's disease to human chromosome 1.

Then it took Bird's colleague, molecular geneticistGerard Schellenberg and his associates about four weeksto clone that gene.

It took the journal Science an unhurried six weeks toaccept Schellenberg's paper reporting that first gene-mapping project, and titled: "A familial Alzheimer'sdisease locus on chromosome 1" But the journal neededonly one fast-track week to accept the second article,"Candidate gene for the chromosome 1 familialAlzheimer's disease locus."

Both accounts appear back to back in today's Science.

Besides senior authors Bird and Schellenberg _ both ofthe Seattle Veterans Affairs Medical Center _ that firstpaper, the story of how linkage analysis tracked theAlzheimer's disease locus to chromosome 1, lists six co-authors. Unnamed are nine American extended familiesof Volga-German ancestry who made that feat of DNAmapping possible.

As Schellenberg recounted to BioWorld Today, "Aroundthe year 1760, a closely knit population of peasantsmigrated from the German principality of Hesse to theVolga river region of Russia, where they settled twovillages. Then, in the late 1800s, some 300,000 to400,000 of these Volga-Germans, as they were called,came in large waves of migration to the U.S. Here, theysettled as farmers in the western plains states."

What brought these people to the attention of ThomasBird a decade ago, Schellenberg continued, was thecurious fact that whereas Alzheimer's disease usuallystrikes after the age of 70, "the Volga-German people gotit fairly early, between 46 and 65 years of age." Asidefrom this early onset, "their Alzheimer's disease signsand symptoms, incidence and prevalence, are identicalwith the late-onset type."

Nine Families Provide Panoply Of DNA

These nine kindred, scattered all over the U.S., andnumbering 106 affected members over two to threegenerations, provided the Seattle molecular geneticistswith a ready-made panoply of DNA sequences and brainautopsies for comparison with samples of the U.S.population at large, in narrowing down the putative early-onset gene, first to the long arm of chromosome 1, then toa specific region on which to deploy positional cloningand other instruments of gene identification andexpression.

Meanwhile, a rival team of molecular geneticists at theUniversity of Toronto, led by veteran Alzheimer's diseaseinvestigator P. H. St. George-Hyslop, had beatenSchellenberg's team to the punch, literally by days. TheToronto group announced, in Nature dated June 29, 1995,"Cloning of a gene [on chromosome 14] bearing mis-sense mutations in early-onset familial Alzheimer'sdisease." (See BioWorld Today, June 29, 1995, p. 1.)

One of that paper's co-authors was molecular geneticistRudolph Tanzi of the Massachusetts General Hospital, inBoston. As Schellenberg recalled, "When the 14 gene,S182, was published, Tanzi put it through the data base ofrandom-sequence DNAs. That's what you do whenyou're trying to figure out the function of a new gene _what it's homologous to."

He continued, "One of these expressed sequence tags[EST] came up with a protein peptide sequence that wasclose to the 14 gene in homology, but not identical. Atthat point, Tanzi and I started to work together."

They made some polymerase chain reaction primers tosee if it might be on chromosome 1. "Not only was it on1," Schellenberg said; "it was on our favorite YAC [yeastartificial chromosome], the one that had the bestmarkers," in the YAC-cloned chromosome 1 Alzheimer'sdisease locus region.

One of those markers in particular seemed promising,Schellenberg said, because "the Volga-German familieshad it, among all of the 160 markers across theirgenotype. And all the people we thought should beinheriting this early-onset form of the disease had onespecific allele [gene variant] at that marker. It was a 112-base-pair fragment, very close to the disease.

"The instant we saw that the gene was on the right YAC,"Schellenberg went on, "we said: `This is a great candidatesequence for an Alzheimer's disease gene mutation." Andit turned out to be a point switch of DNA encodingisoleucine in place of asparagine."

They named the gene thus discovered on chromosome 1"STM," which, Schellenberg said, does not stand for"Schellenberg-Tanzi membrane," but rather, "seven-trans-membrane." This reflects its encoded protein'sseven back-and-forth traverses of the cell membrane.

To achieve this feat of finding the missing early-onsetAlzheimer's disease gene, Schellenberg concluded, "Wekind of pulled out all the stops, and Darwin was really ahuge help."

David Galas is chief scientific officer of DarwinMolecular Inc., in Bothell, Washington. He and two othercompany scientists are among the 19 co-authors on theScience paper describing isolation of the chromosome 1candidate gene.

"We and Schellenberg," Galas told BioWorld Today,"had been planning for some time to go after thechromosome 14 gene and the Volga-German gene. Thenwe got scooped on 14.

Fast-Track Cloning Yields 10 ESTs

"So, following the clue of 14's similarity to the ESTsequence, both our labs got together and went after thecloning on a really crash basis. Darwin ended up doingthe cloning and identification of components _ it's prettyinextricable who did what. We were involved in, let'ssay, the end game."

Galas added, "Now there are 10 ESTs in the public database that are clearly from this gene."

Bothell and Seattle, he continued, "are now trying to doall the obvious follow-up things: Get all the genomicstructure and sequence, find all the other related genes.Construct some mouse models; transfect the gene intocells and look at function.

"Also," he observed, "It's going to be interesting to seehow we scan the large fraction of the population at large,including Alzheimer's disease patients, what othermutations we find in this gene. Whether they correlatewith age of onset, severity of symptoms, and so on.

"At the moment," he concluded, "we are lookingprincipally for cellular genotypes _ the effect of geneson cells _ so we can start screening compounds that maylead us to understanding function, and potentially totherapeutic drug candidates. Nobody knows how far offthat will be." n

-- David N. Leff Science Editor

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