Bethesda, MD-Scientists at the National Human
     Genome Research Institute (NHGRI) at the
     National Institutes of Health (NIH), using the
     recently completed physical map of human
     chromosome 7, have identified an altered gene
     thought to cause as many as ten percent of
          hereditary deafness cases. The findings are
          reported in the December issue of Nature
     Genetics.

     The normal gene makes a protein the researchers
     have named pendrin. The gene is located on
     human chromosome 7, which contains
     approximately five percent of the genes in the
     human genome. When altered, the gene produces
     defective pendrin and causes Pendred syndrome,
     a disorder that typically produces deafness at
     birth due to an improper development of the
     inner ear.

     The finding of the Pendred syndrome gene was a
     three-way collaboration among Dr. Eric D.
     Green's lab at NHGRI, Dr. Val C. Sheffield of the
     Howard Hughes Medical Institute at the University
     of Iowa, and Dr. Benjamin Glaser and his
     colleagues at Hadassah University Hospital in
     Jerusalem.

     In addition to deafness, later in life, Pendred
     syndrome patients develop goiters-abnormal
     swellings in the neck caused by an enlarged
     thyroid gland. Worldwide, the most common
     cause of goiter is lack of iodine in the diet. The
     researchers suspect the underlying defect in
     Pendred syndrome is not lack of iodine, but
     interference of iodine's ability to bind to
     thyroglobulin, a protein produced by the gland
     that is necessary for the synthesis of thyroid
     hormones.

     "This discovery is important since it provides us
     detailed knowledge about a common cause of
     hereditary deafness," said Dr. Green, the paper's
     corresponding author, who heads NHGRI's
     Genome Technology Branch and directed the
     effort to construct a complete map of human
     chromosome 7. "In addition, though, it provides
     us the molecular tools to determine what fraction
     of the deaf population has alterations in this
     gene."

     Because goiter is not always found in Pendred
     syndrome patients, Green said, it is likely that
     alterations in the pendrin gene will turn out to be
     responsible for some cases of deafness that had
     not previously been attributed to this disorder.

     "This outstanding discovery [of the gene for
     Pendred syndrome] illuminates a disorder that
     has confounded scientists for more than a
     century. Pendred syndrome is an important cause
     of congenital hearing loss in children and is
     believed to be underdiagnosed. Finding the gene
     is the beginning of a better basic understanding of
     syndromes affecting hearing," said Dr. James F.
     Battey, Jr., Acting Director and Scientific Director
     of the National Institute on Deafness and Other
     Communication Disorders.

     For their studies, Glaser collected clinical
     information and DNA samples from several large
     Arabic families-Pendred syndrome occurs in all
     ethnic groups-that had a high incidence of the
     disease. Glaser and Sheffield were able to narrow
     down the gene's location to a large interval on
     chromosome 7. Knowing that Green's lab was
     mapping and sequencing that chromosome, they
     solicited Green's help. The detailed physical map
     of chromosome 7 enabled the researchers to
     further narrow the region where the gene was
     situated. Working with Dr. Green at the NIH, Dr.
     Lorraine Everett headed the search for the
     Pendred syndrome gene, an effort that,
     remarkably, took only 13 months, such an
     accomplishment would have taken many years
     prior to the availability of maps, technologies, and
     DNA sequence from the Human Genome Project.

     "This finding is not only important for deafness
     research, but it is also a powerful example of how
     the fruits of the Human Genome Project-in this
     case a map of human chromosome 7-greatly
     simplify the process of finding important disease
     genes," said NHGRI director Dr. Francis Collins.
     "Discoveries like this demonstrate how rapid
     disease gene identification can be as the Human
     Genome Project continues to mine the genome
     for its treasures. As more of the human genome
     is sequenced, it will become much more common
     for disease gene hunters to find a known gene
     waiting for them when they arrive at the
     neighborhood known to contain a disease gene."

     Currently, Green's lab is collaborating with
     colleagues at the Washington University School of
     Medicine in St. Louis who are sequencing the
     chromosome-determining the exact order of the
     "letters" that spell out its genetic code-beginning
     with regions of particular medical importance. As
     chromosome 7 sequences are determined, they
     are posted on the World Wide Web, where they
     are freely available to all researchers.

     "We are working in partnership to get human
     chromosome 7 completely sequenced as part of
     the sequencing phase of the Human Genome
     Project. We found this deafness gene by providing
     the Washington University team with cloned DNA
     fragments from the general region of
     chromosome 7 that we knew contained the gene,
     and then carefully analyzing the data as it was
     generated."

     Recessive genetic disorders like Pendred
     syndrome are caused by genes that contain
     errors, or genetic alterations. To be affected, an
     individual must possess two altered copies of a
     gene-one from each parent. Green likens the
     process of searching for these altered genes to
     that of a proofreader seeking typographical errors
     in a book. As the normal DNA sequences were
     posted, the NHGRI researchers studied the data
     for genes in the way an editor might scan a
     paragraph looking for verbs. "You know a verb is
     where the action is, with the other words being
     decoration."

     Each time they found a gene, they tested to see if
     it was expressed (turned on) in the thyroid, since
     the Pendred syndrome gene was thought to be
     important in this tissue, and if it contained any
     alterations (typographical errors) in Pendred
     syndrome patients. After examining about seven
     genes without success, they found one that was
     heavily expressed in thyroid and was altered in
     Pendred syndrome patients.

     To date, they have uncovered three different
     typographical errors that cause Pendred
     syndrome and suspect they will find more as they
     study additional patients. It is likely that different
     alterations will account for some of the variability
     in symptoms seen among people with Pendred
     syndrome.

     Pendrin, the protein encoded for by the Pendred
     syndrome gene, appears to be responsible for
     transporting sulfate across cell membranes, most
     likely into cells.

     "In only the past few years, scientists have
     discovered three human sulfate transporters-each
     of which was later implicated in human disease.
     And very different kinds of diseases," Green said.
     "In each case, the range of tissues in which the
     gene is expressed is very restricted. So these
     closely related proteins serve different roles in
     different tissues and, when altered, lead to
     distinct diseases.

     One of the other altered sulfate transporter genes
     is responsible for a disease of the gastrointestinal
     tract called congenital chloride diarrhea
     syndrome, while the other causes a severe form
     of dwarfism known as diastrophic dysplasia.

     Scientists don't yet know why sulfate transporters
     appear to be essential for normal function of
     certain tissues, such as thyroid.

     "We can speculate a bit," Green said. "Sulfate is
     often attached to proteins and sugar chains made
     in the thyroid. Maybe if sulfate can't get into the
     cell, it is not available for attachment to these
     products. In turn, these proteins or sugars may
     not function properly if they don't contain sulfate.
     But we don't yet know for certain".

     Sulfate's role in Pendred syndrome's
     characteristic malformation of the inner ear,
     which occurs early in fetal life, is also a mystery.
     Studying the development of the human inner ear
     is very difficult, so the NHGRI researchers are
     already studying this gene in the laboratory
     mouse. They plan to develop a "knockout" mouse,
     inactivating the mouse's normal gene, in order to
     investigate how abnormal inner ear development
     causes deafness in Pendred syndrome.

     "We had virtually no clue about what gene could
     cause both deafness and thyroid disease. That the
     gene encodes a sulfate transporter came as a
     complete surprise." Green said. "When something
     is surprising, however, it also means there is a
     complete new area of human physiology to
     study."

     Other researchers on the paper include Jacquelyn
     Idol and Andreas Baxevanis of NHGRI; Andreas
     Buchs and Ma'ayan Heyman at Hadassah
     University Hospital, Israel; John Beck at the
     University of Iowa; Faiad Adawi at Rikva Zeev
     Hospital, Israel; and Elias Nassir at Western
     Galilee- Nahariya Hospital, Israel.

     NHGRI oversees the NIH's role in the Human
     Genome Project, an international research effort
     to develop tools for gene discovery.

     For interviews or more information contact:

     Jeff Witherly: 301-402-8564
     Galen Perry: 301-402-3035