Clinical Sleuthing Reaps Rewards for U-M Visual Science

Strange as it may seem, a form of the vision-threatening disease glaucoma and a rare orthopedic disorder called Nail-Patella Syndrome have a common molecular history. A research effort headed by scientists at the University of Michigan Department of Ophthalmology and Visual Sciences has shown that these two vastly different disease manifestations are the shared effect of a mutation in a single gene.

Paul Lichter and Julia Richards

Increased pressure in the eye, damage to the optic nerve, and a decrease in the field of vision characterize glaucoma, one of the most common causes of visual loss. When left untreated, glaucoma will rob a person of sight. The National Eye Institute estimates that three million Americans have glaucoma, and that of these, 120,000 are blind. Half the people in whom the disease process has begun do not realize they have glaucoma until irreversible damage has occurred. More than a dozen glaucoma genes have been mapped or cloned so far.

Nail-Patella Syndrome, on the other hand, is rare. Its incidence is one in 50,000 births, and its name derives from two of its most evident characteristics, absent or ridged nails of the hands and absent or small kneecaps (patellae). A variety of other orthopedic features of the disease can affect mobility, and surgery is required in some cases. NPS has long been accepted as a familial disease, and one of the first genetic linkages discovered in humans in the 1950s placed the NPS locus near the ABO blood group genes on chromosome 9. The characteristics of NPS have been reported in the orthopedic literature for more than 100 years, but throughout its long history no one had figured out that glaucoma can be one of the characteristics of the disease.

Physicians and researchers in the Department of Ophthalmology and Visual Sciences discovered the curious association between these two disparate conditions. Paul R. Lichter, M.D., F. Bruce Fralick Professor and chair of the Department of Ophthalmology and Visual Sciences, is a glaucoma specialist who collaborates with basic scientist Julia E. Richards, Ph.D., a molecular geneticist and senior research assistant, in a study of genetic defects underlying the hereditary forms of glaucoma. Together, Richards and Lichter have been tracking the clinical characteristics of glaucoma as part of their study of the relationship between phenotypes and genotypes.

In a classic example of what can be accomplished by a perceptive clinician, Lichter noticed that one of his glaucoma patients had no thumbnails. Lichter remembered that when he had treated this woman’s mother for glaucoma, he had observed a similar lack of thumbnails. “Dr. Lichter made a connection between NPS and glaucoma that had not been made by a century of physicians studying this syndrome. And it’s easy to see why it would have been missed. When a child with NPS goes in to have surgery, the orthopedist has no reason to ask if grandmother uses eye drops,” says Richards. Further investigation showed that six family members had glaucoma plus NPS, and that a similar association between the two diseases was present in a second family.

Lichter and Richards teamed up with Michael Boehnke, Ph.D., in the Medical School’s Department of Biostatistics to evaluate the relationship between NPS and glaucoma. Linkage analysis provided strong evidence of a genetic relationship between NPS and glaucoma, and showed that NPS in these families was linked to the known NPS locus on chromosome 9. To answer additional questions, however, identification of the actual NPS gene was needed. Collaboration with Iain McIntosh, Ph.D., at Johns Hopkins University resulted in isolation of a “contig,” an overlapping set of clones spanning the region of chromosome 9 that contained the NPS gene.

Another collaboration, this time with Douglas Vollrath, M.D., Ph.D., at Stanford University led to the determination that the NPS gene is the human transcription factor gene LMX1B. “Dr. Vollrath called us to suggest LMX1B as a candidate NPS gene based on its location and its functional characteristics,” says Richards. “When tests showed it was present at the right location in the contig of clones, we were off and running to clone and sequence the gene and test for mutations in the patients. It was a very exciting time and everything happened rather quickly after that.”

Since then, the Michigan-Stanford collaboration has found mutations in a dozen NPS families and has shown that the glaucoma and orthopedic characteristics present in a given family are likely both the result of the same mutation in LMX1B. Many questions remain to be answered about the level of glaucoma risk faced by someone affected by NPS, since there are NPS families in which glaucoma is not found. However, it is clear that glaucoma is not a rare finding among older individuals with the syndrome, and people with NPS should be made aware of their risk of glaucoma. A recent paper co-authored with U-M orthopedist Frances Farley, M.D., has alerted the orthopedics community to the importance of referring NPS patients for glaucoma screening.

This kind of collaboration between basic scientists and clinicians can identify underlying genetic defects and pave the way to a better understanding of diseases. In this case it revealed a relationship between the orthopedic and ocular characteristics of NPS.

Lichter can be contacted at plichter@ umich.edu, Richards at richj@umich.edu.