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: 301-4028564
Galen Perry: 301-40-3035.
Additional information is available after embargo (December 1, 1997 @ 5 pm.) on the NHGRI website at: http://www.nhgri.nih.gov/NEWS/news.html
Website information includes graphics, high quality audio files of researchers speaking candidly about the discovery, and related background information.
The entire text of the press release is available in electronic form at the website with hyperlinks to supporting graphics, the scientific journal, and researchers/collaborators.