Researchers Identify Inherited Obesity, Retinal Dystrophy Gene

The first gene linked to a complex disorder called Bardet-Biedl syndrome could provide clues to common health problems in the general population, including obesity, kidney disease, blindness and mental retardation.

In the September issue of the scientific journal Nature Genetics, an international team of investigators led by Baylor College of Medicine's Drs. Nicholas Katsanis, Richard A. Lewis and James R. Lupski identify the first of at least seven genes responsible for the disorder. BBS is a rare medical condition characterized by profound weight gain, extra fingers and toes and vision problems that lead to blindness as well as a host of other health problems such as diabetes and kidney dysfunction.

"Finding the genetic cause of BBS has been extremely challenging," said Katsanis, with the department of molecular and human genetics. "We zeroed in on the general vicinity of several BBS genes but identifying which one was defective proved to be a difficult task."

Despite years of intensive research, identification of the gene still eluded researchers until the recent announcement of a gene responsible for McKusick-Kaufman syndrome, another rare disorder that shares some similarities with BBS.

"Our collaborators produced evidence that another BBS gene exists on chromosome 20," Katsanis said, referring to Dr. William S. Davidson's team at Memorial University in Newfoundland. "We then made the observation that MKKS lies in the same area."

Working in the Lupski lab, Dr. Philip Beales, on sabbatical from University College London; Mike Woods, from Memorial University; and Katsanis identified mutations in five Newfoundland and two European-American families with a history of BBS.

"It's been a long road, but we can now start thinking about this syndrome and its implications in the function of many processes, like weight regulation and limb and kidney formation, in a whole new way," Katsanis said.

"The involvement of MKKS could accelerate the identification of other BBS genes," said Lewis, a professor in the departments of ophthalmology and molecular and human genetics, who has been studying this disorder since 1985. "This new development should give us a better understanding of the disorder. One day, it might even provide the chance to intervene in some of the conditions observed in BBS, such as retinal disease, which appears even before the child is several years old. This information also should give us a better understanding of the molecular mechanisms that govern the regulation of body fat as well as limb and kidney development."

BBS affects people around the world; however, it is five times more common in Saudi Arabia, Kuwait and Newfoundland, affecting as many as 1 in 25,000 people. Researchers believe that about 40 percent of the BBS population in Newfoundland carry mutations in MKKS, an observation critical for prenatal diagnosis of the condition on the island.

The gene for BBS appears to be a chaperonin, a protein responsible for folding other proteins once they are produced. Improperly folded proteins cannot perform their designated functions and lead to disease.

"We study rare diseases because they are the best way to model common conditions. Involvement of protein folding in BBS has been surprising and exciting at the same time. We can now start thinking about what type of proteins this molecule folds, which will provide important clues to the processes that malfunction in BBS, such as obesity, diabetes, retinal dystrophy and mental retardation," explained Lupski, professor of molecular and human genetics.

Co-authors on this study also included Drs. Jane S. Green and Patrick S. Parfrey, with Memorial University, who for many years collected and characterized BBS families from that region, and Stephen J. Ansley, with Baylor.

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©2006 Texas Medical Center

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