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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 identify 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
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.
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
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.