Hopkins Researchers Find Genetic Cause For Multi-system Disorder

Studying genetic samples and medical histories from 17 families with the syndrome, known as oculodentodigital dysplasia, the scientists discovered that changes in a gene called connexin 43 are to blame for the disorder, which also can include hearing loss, heart trouble and neurological problems. The findings, published online ahead of print, will appear in the February issue of the American Journal of Human Genetics.

"It's pretty amazing that it's taken so long to link a connexin gene to a disorder that affects so many of the body's systems," says Ethylin Jabs, M.D., director of Hopkins' Center for Craniofacial Development and Disorders and a member of the school's McKusick-Nathans Institute for Genetic Medicine. "Connexin 43 and related genes are present in many tissues during development, but until now problems with connexins had only been tied to simpler manifestations."

A family of roughly 20 genes, connexins are best known for creating connections between cells, bridging space called a "gap junction," notes lead author William Paznekas. When connexins on one cell interact with connexins on a neighboring cell, the result is a direct line of communication. The researchers emphasize that other genes -- possibly even other connexins – or environmental factors likely account for the variety of effects seen in patients.

Since connexin 43 is turned on in fetal development in a pattern that reflects the problems seen in oculodentodigital dysplasia, the scientists suspected its involvement in the disorder. They determined the sequence of its building blocks in affected and unaffected members of 17 families in the United States, the Netherlands, Norway and Turkey, and in 100 additional people. Only people with the disorder had changes in connexin 43, the researchers report.

A different change, or mutation, in the gene was found in each of the 17 families, but all changes altered the instructions to make the connexin 43 protein, the researchers discovered. While the changes' exact effects on the protein remain to be studied, they likely alter the nature of the communication bridge, says Jabs, who is the Frank V. Sutland Professor of Pediatric Genetics at Johns Hopkins.

The discovery should help improve understanding of how connexins contribute to the crucial signaling processes that underlie normal development, the researchers say, and may also one day lead to a genetic test for families with a history of the disorder.

Because of their widespread presence in cells during critical developmental periods, problems with connexin genes (and the proteins made from their instructions) have already been tied to a number of inherited conditions involving deafness or peripheral neuropathy. While others have linked a connexin to Charcot-Marie-Tooth disease, Jabs and her colleagues have helped identify a faulty connexin gene as the cause of a skin and deafness disorder known as "KIDS" (for keratitis, ichthyosis and deafness syndrome).

Other authors on the report are Simeon Boyadjiev of Johns Hopkins; Robert Shapiro, University of Vermont College of Medicine; Otto Daniels, Children's Heart Centre, Nijmegen, the Netherlands; Bernd Wollnik of the Child Health Institute, Istanbul, Turkey; Catherine Keegan and Jeffrey Innis, University of Michigan; Mary Beth Dinulos, Dartmouth-Hitchcock Medical Center; Cathy Christian, Kaiser Permanente, San Francisco; and Mark Hannibal, University of Washington, Seattle. The work was funded by the U.S. National Institutes of Health.