Mice help nail down gene for rare syndrome.

Randy L. Johnson is interested in how limbs form, so he wondered what would happen if mice lacked a gene related to one implicated in the development of chicken limbs. Much to Johnson's surprise, his studies of such mutant mice have led to the identification of the gene responsible for a rare human disorder called nail-patella syndrome (NPS).

For more than a century, physicians have recognized this curious syndrome in which people have, to varying degrees, abnormal growth of fingernails, toenails, and knee caps, or patellae. At the extreme, people with NPS have no knee caps or nails whatsoever. Some 50 years ago, physicians linked kidney problems, often severe enough to require transplants, to the syndrome. Last year, investigators also noticed that people with the syndrome frequently have the eye disorder glaucoma.

Scientists have been puzzled by this odd collection of symptoms and have even pondered whether more than one gene must be involved. At the Society for Developmental Biology meeting last week in Palo Alto, Calif., Johnson, who works at the University of Texas M.D. Anderson Cancer Center in Houston, explained how the findings on his mutant mice strongly indicate that a single gene is behind NPS. Some of his team's results are also described in the May Nature Genetics.

To create the mutant animals, the scientists deactivated both copies of a mouse gene called Lmx1b. It encodes a transcription factor, a DNA-binding protein regulating the activity of genes. The resulting mice, which survive less than a day after birth, lack patellae and nails. Further examination revealed kidney abnormalities as well.

The gene's link to NPS grew stronger when the researchers realized that the human version of Lmx1b maps to the exact region of chromosome 9 where the syndrome's mutant gene is thought to reside. Finally, working with a research team led by Brendan Lee of Baylor College of Medicine in Houston, Johnson's group found that three people with NPS harbor mutations in the gene and their unaffected parents do not.

Curiously, it takes mutations in both copies of Lmx1b to produce symptoms in mice, although a defect in just one is sufficient to cause NPS in people. The amount of transcription factor produced may be crucial to the human disorder, which could explain why people with similar mutations are afflicted to different degrees, says Johnson.

"We want to get a handle on what causes the variation," adds lain McIntosh of Johns Hopkins Medical Institutions in Baltimore, who is leading a study of people with NPS. "There's nothing jumping out and saying that certain types of mutations cause certain aspects of the [syndrome]."

The connection between glaucoma and NPS has been strengthened by the discovery of Lmx1b's involvement. At last week's meeting, Johnson reported that the normal gene is active in the eyes of mice.

A second research group, made up of scientists from Stanford University and the University of Michigan in Ann Arbor, has independently identified the nail-patella gene by studying families with members who have both the syndrome and glaucoma. That group, led by Stanford geneticist Douglas Vollrath, is publishing its results in the July Human Molecular Genetics.

Since the condition is so variable, physicians sometimes have trouble diagnosing whether a patient has NPS. Testing for mutations should resolve any confusion. "There is real potential to having this gene in hand," notes Vollrath. "Anyone with nail-patella syndrome should be tested for glaucoma." The eye disorder is still incurable, but some therapies slow its progression, he explains.

There's also a possibility, says McIntosh, that NPS's kidney problems and glaucoma would be treatable if the defects turn out to be reversible and if scientists could compensate for the dearth of the key transcription factor.