People born with Down syndrome suffer a grim spectrum of problems, including mental retardation, immune and endocrine system abnormalities, and skeletal, heart, and digestive system defects. Because those affected--about one in 800 newborns--usually have an extra copy of all or part of human chromosome 21, sorting out which of the many extra genes cause these symptoms has been difficult. But now several research teams have homed in on a gene that may contribute to one aspect of Down syndrome, the brain defects.

The work suggests that having either too much or too little of the gene's protein product, an enzyme called DYRK for dual specificity tyrosine phosphorylation-regulated kinase (Y denotes tyrosine), disrupts brain development. "This is a gene [for which] dosage plays an important role in how the neuronal pathways are put together," says geneticist Edward Rubin of the Lawrence Berkeley National Laboratory in Berkeley, California.

Woo-Joo Song and David Kurnit, molecular biologists at the University of Michigan Medical Center in Ann Arbor, linked the DYRK gene to the mental symptoms of Down's while following up on a discovery made last year by Olaf Pongs and his colleagues at the Center for Molecular Neurobiology in Hamburg, Germany. Those researchers had identified a strain of mutant fruit flies that have smaller than normal brains and impaired learning as a result of a defect in a gene they called minibrain. That gene's sequence indicated that its protein product is a new type of kinase enzyme that may control cell division.

Thinking that a similar human gene might be involved in the mental retardation of Down syndrome, Song used the sequence of minibrain to probe for its human equivalent on a region of chromosome 21 that appears critical for Down syndrome, as it is the only extra genetic material found in some patients. He reported at the cell biology meeting that he indeed found the gene there. Other teams in Japan, Spain, and the United States have come up with the same result, Song adds.

By itself, that finding doesn't prove that excess DYRK causes Down's problems; the critical chromosome 21 region contains about 50 genes in all. But the Song team also found that in mouse embryos, the DYRK gene is expressed in the same places--areas such as the gray matter of the brain, the spinal cord, and the retina--that are defective in Down syndrome.

Instead of doing a genetic search for key Down syndrome genes, Rubin and colleague Desmond Smith at the Lawrence Berkeley lab homed in on DYRK by looking at the behavior of several new strains of mice, each carrying a part of the crucial human chromosome 21 region. One strain, which did poorly in simple learning tests, contained a stretch of human DNA 180 kilobases long that includes DYRK, Smith and his colleagues reported in late October at the American Society of Human Genetics meeting in San Francisco. "It's like a pincer movement," he says. "We both landed on the same gene."

The two prongs of the pincer show that any departure from the gene's normal activity level can be dangerous. The mice's problems, like those of Down's patients, were caused by an extra copy of the DYRK gene, while the mutant fruit fly's were caused by having too little of minibrain's protein product. "You need exactly two copies of the gene," Smith concludes. He cautions, though, that more work is needed to confirm that DYRK is the gene at fault in the 180-kilobase region.

Assuming that it is, it's unlikely to work alone. Using mouse genetic engineering studies similar to those of Rubin and Smith, a French team, led by Dahmane Nadia of the Hospital Necker in Paris, has found that another chromosome 21 gene, which lies outside the 180-kilobase region and is the human equivalent of the fruit-fly single-minded gene, seems to lead to learning problems in mice with an extra copy. Sorting out how these two genes, and possibly others, contribute to Down's and to normal neural development, says Smith, is going to make "for a very exciting next few months."