Emory Report

August 28, 2000

 Volume 53, No. 1

Grant helps Sherman focus on Down syndrome

By Holly Korschun

Although scientists have known for more than 30 years that Down syndrome results from having three copies of chromosome 21 instead of the normal two, they still know surprisingly little about why or when the chromosome error occurs. Moreover, they still do not understand why the increase in the number of chromosome 21 genes leads to the particular birth defects and varied health problems suffered by individuals with Down syndrome.

A group of scientists and research institutions led by Emory and geneticist Stephanie Sherman will use a $6 million grant from the National Institutes of Health (NIH) to help find the answers to these questions.

The most common cause of Down syndrome is nondisjunction of the chromosomes 21 resulting in "trisomy 21." This occurs during the formation of gametes, when the chromosome number is reduced from 46 chromosomes to 23, a process called meiosis.

In cases of trisomy 21, the pair of chromosomes 21 do not separate properly (that is, they "nondisjoin"), creating an abnormal egg or sperm. When an abnormal egg or sperm cell containing an extra chromosome 21 merges with a normal egg or sperm cell, the resulting fertilized cell contains three chromosomes 21 rather than two.

Sherman views Down syndrome not as a single entity but as subgroups of conditions defined by the timing of the chromosome error and its parental origin. Although scientists are certain that maternal age is by far the biggest risk factor for Down syndrome, Sherman and her colleagues are using molecular and epidemiologic studies to help understand the origin of the maternal age effect. Although not as important, risk factors other than age may help the scientists uncover the mechanisms of trisomy 21, Sherman believes.

"For example, in our previous studies over the past 12 years, we have found preliminary evidence that women who smoke and take oral contraceptives right around the time of conception have an increased risk for a chromosomal error of a certain type," she said.

"We know that when an egg is recruited for ovulation, a new vascular system is built around the follicle," Sherman continued. "Perhaps that process is disrupted by smoking or oral contraceptive use, leading to reduced oxygen flow into the egg. If true, this suggests that the maternal age effect, in general, could be due to problems of the level of oxygen going into the follicle in an aging ovary."

In previous research, Sherman found that altered recombination along a nondisjoined chromosome 21 is associated with increased risk for all types of errors in meiosis. In their current research, she and her colleagues are investigating the relationship of this altered recombination to maternal age, as well as looking at the levels of recombination in the rest of the chromosomes of the abnormal egg to better define the risk factor for nondisjunction.

In addition, Sherman's research will begin to investigate why some children with Down syndrome have specific association birth defects (such as congenital heart defects or an increased risk for leukemia) and others do not. They will begin to look at genes located on chromosome 21 to identify candidate genes that may be involved in these developmental processes. They also will study environmental risk factors and their interactions with identified susceptibility genes.

The chromosome research will require the involvement of a large number of individuals with Down syndrome and their families-more than 1,350 cases of trisomy 21 collected through birth defects surveillance systems throughout the United States. In addition to obtaining DNA samples from case families, interviews of parents of cases and controls will be conducted.

The six sites included in the new NIH grant also are part of a National Birth Defects Prevention Study sponsored by the Centers for Disease Control and Prevention (CDC). They include the Metropolitan Atlanta Congenital Birth Defects Program (conducted by the CDC), the University of Arkansas for Medical Sciences, the California Department of Health Services, the University of Iowa, the New Jersey Department of Health and the New York Department of Health.

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