Researchers map gene for connective tissue disease

Researchers from UNMC and the Center for Genomic Sciences at Allegheny Singer Research Institute in Pittsburgh have identified the location of a gene on the human genome that is responsible for Dupuytren's contracture, the most common inherited connective tissue disease. The team's discovery recently was published in the journal Clinical Genetics.

Dupuytren's contracture is a soft tissue disease that affects the palmar fascia, the thick connective tissue that lies above the tendons and beneath the skin in the palm of the hand. Through its attachment to both the tendons and skin, the palmar fascia works as an anchor, facilitating the hand's ability to grasp or manipulate objects.

Dupuytren's contracture is a progressive thickening and shortening of the palmar fascia, causing a permanent flexing of the fingers that can significantly impair the hand's functioning, said Garth Ehrlich, Ph.D., scientific director of ASRI's Center for Genomic Sciences and a principal investigator in the study.

"Duypuytren's contracture is the most common simple genetic trait that has yet to be genetically mapped. Although its cause is not completely understood, it is believed that the disease results from a defect in the body's normal wound healing response. Understanding its genetic origins therefore, will likely provide insights into a host of other similarly characterized diseases," Dr. Ehrlich said.

Clinical signs of Dupuytren's contracture are typically first noted in the fifth or sixth decade of life and disease progression is variable. While all fingers can become involved, the disorder most often affects the ring and little fingers. Usually painless, the condition can be debilitating as affected fingers bend towards the palm and cannot be straightened.

Though the hereditary form of Dupuytren's contracture is most prevalent in Scandinavia and among Scandinavian immigrant populations, the disease is found among all ethnic groups. The disease is more common among men than women.

Collaborating with researchers from the Universities of Linkoping and Umea in Sweden, a team led by Dr. Ehrlich and N. Ake Nystrom, M.D., Ph.D., a hand surgeon in the UNMC Department of Orthopaedic Surgery, identified a five-generation Swedish family with a genetic history of Dupuytren's contracture by age 60.

Blood samples were collected from all affected and informative unaffected family members for the performance of a genome-wide assessment. The analysis mapped a gene for Dupuytren's contracture to human chromosome 16q.

"We have essentially identified a single small region within the vast human genome where the gene for this disease exists. Efforts are now underway to identify the gene itself. Once that is accomplished, the next step would be to develop a better, less invasive method of treating it," Dr. Nystrom said.

There is currently no known way to alter the course of Dupuytren's contracture once it begins. Standard treatment for the disease is a surgical procedure known as fasciectomy, in which segments of the palmar fascia are removed.

Complications with surgery, however, are common, Dr. Nystrom said, as Dupuytren's tends to envelop adjacent structures as well, particularly the small nerves of the hands and fingers.

"Dissection of the palmar fascia is often slow and tedious and injury to nerves is a serious potential complication. Even if a procedure goes well, the contracture still may return months or years after surgery. Better understanding of the genetics of this disease will hopefully move us in the direction of a more effective therapeutic approach," Dr. Nystrom said.

Funding for this research was provided by Allegheny Singer Research Foundation and by grants from the National Institutes of Health.