August 28, 2000
Volume XXXIII, No. 32

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UTHSC researchers map gene for rare inherited disorder 

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Medicine

The term genetic research may conjure up images of haphazard trials resulting in human clones or abnormal life forms. In real life, however, gene research is hard work focusing on the prevention of inherited disorders. Specifically, gene mapping, a powerful technique used in modern molecular genetics, helps identify unknown genes in families with a particular inherited disorder, which includes many psychiatric diseases. This is the first step in understanding the biology and designing treatments for those disorders.

Finding and then charting the location of a particular gene can be difficult, painstaking work and take years. Yet in a little more than a year, Dr. Michael Escamilla, psychiatry, and his genetic research team have zeroed in on the location of a gene that causes acheiropodia, a rare genetic disease characterized by the absence of hands and feet.

"There’s been a revolution the last couple of years in finding the genes that cause disorders," said Dr. Escamilla, a board-certified psychiatrist with 17 years of genetic research experience. "Mapping and sequencing genes used to take several years. Now because of the work done by the Human Genome Project, which has already sequenced more than 90 percent of the work done in the past by individuals, we’ve mapped the location of the gene for acheiropodia."

What’s more, the Health Science Center investigators did so with only the minimum amount of samples. Dr. Escamilla and his team performed a complete genome screen of seven members of an extended Brazilian family that included three siblings with the deforming disease. They used the "homozygosity mapping" technique.

"Homozygosity mapping has been successfully used to map rare autosomal recessive diseases with a minimal number of affected cases," said Dr. Escamilla, a native San Antonian and a recently appointed faculty member in the Department of Psychiatry. "This special technique was used to first identify two regions, on chromosomes 14 and 7, which were most likely to harbor the gene. Additional experiments then clarified that the acheiropodia gene is located on 7q."

Dr. Michael Escamilla (left) and his genetic research team, which includes Dr. Edna Torgyekes (center) and lab assistant Sophia Rodriguez (right), have zeroed in on the location of a gene that causes a rare genetic disease.

A homozygote is a person who carries two copies of a defective gene. In this case, it was the gene for acheiropodia, a recessive disease observed in multiple members of inbred Brazilian kindred of Portuguese ancestry. The families in the study come from São Paulo and Santa Catarina, estimated to be the most likely center of origin of the disease mutation. The affected individuals are missing forearms, hands and feet. Two of the individuals had one digit implanted bilaterally into each humeral stump.

"This disease usually seems to happen among inbred families; the parents of the three siblings were first cousins," said Dr. Escamilla, who points out that a recessive disease has two bad genes passed down the family tree. "Our goal was to see how the DNA in each person in the family migrated and see how the disease was inherited."

Gene mapping, also known as "genetic linkage," allows researchers to look for new genes in families in which several members are affected with a particular disease. Using genetic markers as "signposts," researchers compare about 400 of the markers within families and look for locations where all affected individuals carry the same signposts.

The locations are given a score. If it is greater than 3, then it becomes highly unlikely that this association happened by chance. More important, this evidence clearly defines where the gene resides. The challenge is to look in that region of the chromosome indicated by the mapped marker and identify the exact gene, and then a mutation, that’s responsible for the disease in a given family.