More Clues to Pendred Syndrome

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Release: Immediate May 26, 1999

UI researchers find more clues to Pendred syndrome

IOWA CITY, Iowa -- A University of Iowa study has advanced understanding of Pendred syndrome, an inherited condition that causes deafness, usually at birth, and development of goiter -- an enlarged thyroid -- in childhood.

The UI researchers used cell cultures to study the transport mechanism of pendrin, a protein associated with Pendred syndrome. In people with the condition, a Pendred gene mutation produces a defective form of the protein. A previous UI study helped identified this gene that normally produces pendrin, but investigators did not determine how the protein might contribute to Pendred syndrome.

"Because of the protein's structure, most researchers, ourselves included, first believed that pendrin transported sulfate into and out of cells," said Lawrence P. Karniski, M.D., UI associate professor of internal medicine and lead investigator of the more recent study. "Instead, we found that pendrin functions to transport iodide and chloride across cell membranes."

Karniski said that after months of looking unsuccessfully for sulfate transport, the UI team decided to investigate negatively charged ions other than sulfate and chose iodide because of its connection to goiter. The researchers found that pendrin is likely responsible for the last step in iodide transport in the thyroid, before the iodide is incorporated into thyroid hormones. For people with Pendred syndrome, a defect in iodide transport may cause the thyroid to enlarge, although the thyroid will usually continue to function normally.

Iodide is probably not involved in normal ear function, Karniski said. "So we looked at molecules in nature that are structurally related to iodide and found that pendrin also transports chloride."

Karniski said the discovery is the "first clue" that a defect in chloride transport may cause the deafness, the most debilitating part of Pendred syndrome.

"Different concentrations of electrolytes -- potassium, sodium and chloride -- are normally found in different compartments of the inner ear," Karniski explained. "If any of these electrolyte concentrations are disturbed, the ability of the inner ear to transfer sound waves to the brain can be lost."

People with Pendred syndrome have different degrees of hearing loss, but it is severe for more than 50 percent of them. Karniski said the syndrome is probably the most common form of deafness that is not isolated but appears with another condition, in this case, goiter.

The findings could eventually lead to strategies aimed at correcting the chloride and iodide transport abnormalities caused by the underlying genetic defect, Karniski said. Using cell culture systems, the researchers will next study the known genetic mutations found in Pendred syndrome.

The UI team included Trisha M. Kreman, research assistant in internal medicine; Daryl A. Scott, a UI Medical Scientist Training Program student in the Genetics Ph.D. Program; Val C. Sheffield, M.D., Ph.D., UI professor of pediatrics and a Howard Hughes Medical Institute investigator; and Rong Wang, research assistant in internal medicine. In 1997, Sheffield led a UI team as part of an international effort that identified the defective gene in Pendred syndrome.

The more recent study was funded in part by grants from the Office of Research and Development in the Department of Veterans Affairs and from the National Institutes of Health. The findings were published in the April issue of Nature Genetics.

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