Unexplored role for skin gene in brain.

Elaine Fuchs, a Howard Hughes Medical Institute (HHMI) researcher at the University of Chicago, has successfully tracked down genetic flaws that underlie many human skin disorders (SN: 9/28/91, p.197). Lately, she has concentrated on a gene known as BPAG1, which has been implicated in a blistering disease called bullous pemphigold (BP). That focus led her on an unexpected foray into neurobiology.

Initially, Fuchs and her colleagues disabled the BPAG1 gene in a strain of mice, thus crafting animals that do not make the BPAG1 protein. The researchers thought this protein linked the intricate network of keratin  filaments inside each skin cell to certain molecules in the cell membrane. As predicted, in mice with the disabled gene, "we've cleanly severed the connection to the keratin filaments,'' says Fuchs. The mice do not experience the same problems as BP patients, but their skin cells are more fragile and wounds heal slowly, the researchers report in the April 21 Cell. The surprise appeared when the mice matured. "All of a sudden, their central nervous system goes to pot. By 5 weeks, their limbs are absolutely useless,'' says Fuchs.

That progression and the pattern of destruction found in the animals' brains at autopsy suggested dystonia musculorum, an inherited neurodegenerative disease in mice. When Fuchs' team studied a strain of mice with this disease, they found flawed BPAG1 genes.

Fuchs' group theorized that the BPAG1 gene yields a slightly different protein when expressed in the brain rather than the skin. That suspicion has now been borne out by a Canadian research team that has chased the genetic cause of dystonia musculorum for more than 9 years.

Arthur Brown, Rashmi Kothary, and their colleagues at the Cancer Institute of Montreal confirm BPAG1's importance in a report to be published in the July Nature Genetics. They also show that, in neurons, the gene produces at least two proteins different from the one made in skin cells. The race is on now to find out what these brain-specific proteins do and whether errors in the human version of the gene that encodes them contribute to known neurological illnesses. "It's a gene looking for a disease,'' says Kothary.