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Release: May 30, 2001

UI researchers identify mutated genes associated with obesity, diabetes

IOWA CITY, Iowa -- An international research team led by University of Iowa Health Care investigators has identified two mutated genes that cause certain features of a rare, recessive inherited disorder called Bardet-Biedl Syndrome (BBS).

While the syndrome occurs in less than one in 10,000 persons, the genetic findings, known as BBS2 and BBS4, have implications for understanding obesity, diabetes and hypertension (high blood pressure) in the general population, said the study's principal investigator Val Sheffield, M.D., Ph.D., UI professor of pediatrics and a Howard Hughes Medical Institute associate investigator. Edwin Stone, M.D., Ph.D., UI professor of ophthalmology and visual sciences, served as co-principal investigator for the studies.

The BBS2 genetic findings were published in the April 1 issue of Human Molecular Genetics and are available online at The BBS4 genetic findings will appear in the June 1 issue of Nature Genetics. An abstract will be available online at

"Our findings give us new clues into understanding a variety of processes in human development," Sheffield said. "By continuing to study the BBS2 and BBS4 genes and figuring out precisely what they do, we may gain insight into what pathways are involved in an array of different developmental processes, including processes involved in common conditions such as obesity, diabetes and hypertension."

In addition to causing those conditions, BBS is associated with characteristics that are rarer in the general population, such as mental retardation, polydactyly (additional fingers or toes), kidney problems, heart defects and a blinding disorder known as retinitis pigmentosa. The BBS condition is found in several families in Israel and the Mediterranean.

Previous genetic research indicated there are at least six different genes that, when mutated or altered, independently cause BBS. In other words, not every person with BBS has the same genetic defect or defects.

The first BBS-related gene, known as MKKS, was identified last fall by Sheffield and other researchers in collaboration with investigators at the National Institutes of Health.

"The MKKS gene normally codes for a protein called a chaperonin that helps other proteins to fold correctly," Sheffield said. However, in some people with BBS, the MKKS gene is mutated.

Sheffield added that the MKKS finding made the researchers think the other five genes that cause BBS might also be defective chaperonin genes. However, when the team specifically looked for these in the genetic material where they knew the five other genes were, they did not find any mutated chaperonins.

"So we went back to our strategy of analyzing a variety of genes found within specific chromosomal regions linked to BBS in large families from Israel," Sheffield said.

The first finding was the mutated BBS2 gene, which is located on chromosome 16. Next, the team found BBS4, which is located on chromosome 15 and also is mutated in some people with BBS.

Since the BBS2 and BBS4 genes do not appear to function in the same way as the MKKS gene, it raises the question of how they biologically affect human development, Sheffield said.

As a result, the researchers will need to study how the two genes affect proteins that regulate other proteins and thus have a "cascade effect" on other genes.

"We don't know what the normal function of BBS4 is except that it has some similarity to plants' genes known to play a role in transferring sugar molecules onto certain proteins," Sheffield said. "BBS4 could regulate these proteins by changing their structures and thus have a downstream affect on other proteins."

"While our recent findings don't provide all the answers, the research opens up important new questions and new avenues to pursue," he added.

The Molecular Ophthalmology Laboratory of Edwin Stone and the Genetics Institute at the Soroka Medical Center of Ben Gurion University of the Negev in Beer-Sheva, Israel, headed by Rivka Carmi, M.D., were among the groups collaborating on both the BBS2 and BBS4 gene studies. In addition, a research team led by Alan F. Wright of the Medical Research Council Human Genetics Unit at Western General Hospital in Edinburgh, Scotland, contributed to the BBS4 investigation.

Other UI researchers who played key roles in this research included: Darryl Nishimura, Ph.D., associate research scientist in pediatrics; Kirk Mykytyn, Ph.D., postdoctoral fellow in pediatrics; Terry Braun, graduate student in the genetics Ph.D. program; Charles Searby, research technician in the Howard Hughes Medical Institute; Gretel Beck, research technician affiliated with pediatrics; and Thomas Casavant, Ph.D., professor of computer and electrical engineering in the UI College of Engineering.

Both research projects were supported in part by grants from National Institutes of Health, Foundation Fighting Blindness, Carver Endowment for Molecular Ophthalmology, and Research to Prevent Blindness. The BBS4 investigation was additionally funded by the British Retinitis Pigmentosa Society.

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