It took doctors a year to properly diagnose that Randy Alexander wassuffering from hemochromatosis. His father died shortly afterward,never having been diagnosed with the same iron overload disease.

The condition also was diagnosed in Alexander's brother and sisterbut not until doctors first mistakenly treated his brother with ironpills, thinking he was anemic. The Alexander family's experiencewith the hereditary disease is all too common for the disorder that'streatable if diagnosed early enough.

Alexander recently co-founded the Common Ground Institute forIron Overload Diseases in Greenville, S.C. He was visiting MercatorGenetics Inc., in Menlo Park, Calif., Thursday following the recentdiscovery by scientists there of the gene associated with hereditaryhemochromatosis (HH).

"Mercator has generated an enormous light on the darkness of ironoverload," Alexander said. "This is going to help doctors say, `Yes,you have it,' or `No, you don't.' It has generated the greatest amountof hope."

The HH gene discovery is the first for privately held Mercator, whichalso has gene-discovery programs ongoing in asthma, schizophreniaand cardiovascular disease. The company's discovery of the gene isreported in the August issue of Nature Genetics.

Mercator focused on hemochromatosis because it is a commondisease, affecting as many as one million people in the U.S., and it'slife-threatening, said President and CEO Elliott Sigal. "There aretherapies that save lives," he said, "but it's under-diagnosed."

The paper describes a 178-patient study that showed one single basepair difference detects about 80 percent of the patients. Detection oftwo mutations allowed for diagnosis of 87 percent of HH patients,Sigal said.

Mercator now is developing a diagnostic test for HH. Hopefully a testcan be available to physicians on an investigational basis within ayear, Sigal said. Mercator is in discussions with potential partners."This may have major medical implications soon," he said.

HH now is diagnosed by a blood test that measures the percentage oftransferrin saturation, which is the total serum iron level divided bythe blood's total iron binding capacity. Another blood test measuresiron protein complexes in the blood. But HH often goes undiagnoseduntil damage already has been done to organs. The condition can betreated by regularly removing blood until iron stores are reduced tonormal, then doing the procedure occasionally as maintenancetherapy.

"We need more experience in clinical settings to develop anunderstanding on where this can give improved health care options,"Sigal said. "Our goal is to reach the largest market and make the bestdevelopment plan for what we think will be a widely used genetictest."

Mercator, founded about three years ago, uses several positionalcloning techniques in its discovery effort. One, called "identity bydescent," involves the inheritance of a small segment ofchromosomes that have been passed down many generations from asingle founder, rather than standard genetic linkage analysis fromfamilies.

All In The Family

Sigal said 85 percent of those with HH are related, even though theydon't know it, to one person who had the disease. Therefore theycarry not only the same DNA mutation but a patch of distinct, ancientDNA surrounding it. Mercator then went about seeking the DNAsegment in the 178 HH patients.

What started as a look at a region with 8.5 million base pairs wasreduced to 250,000 base pairs by detecting the smallest commondenominator among the regions. The 250,000 base pairs then werefully sequenced and compared to individuals with the disease.

One particular mutation was found in a novel cDNA that was notcommon in the random population (3 percent) but existed in 85percent of the disease chromosomes, Sigal said. "That associationwas our first evidence this particular gene was the disease gene," hesaid.

The gene, called HLA-H, is a member of the gene family calledmajor histocompatibility complex class I protein. Those genes,Mercator said, are known to interact with a second molecule that,when defective in mice, results in iron overload. One of the identifiedmutations is predicted to have deleterious effects on the function ofthe HLA-H gene.

As part of the gene hunt Mercator had to create its own high-resolution map for the disease region because of gaps in the genomicdata base at the Whitehead Institute in Cambridge, Mass.

"People who have been involved with this for years are elated,"Alexander said. "It's going to save lives and also enhance the qualityof lives." n

-- Jim Shrine

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