Some members of this family lost their hearing gradually, beginning in their twenties and thirties. By the time they reached their fifties, most of the affected family members experienced a debilitating moderate to severe hearing loss. No other characteristics were associated with the deafness. In the general population this hearing loss is similar to the gradual, age-related hearing loss that many people experience in their seventies and eighties.
"Discovery of this family offered an opportunity to identify a gene which is important for maintenance of the auditory system," said Thomas B. Friedman, Ph.D., one of the investigators of the study and chief of the Laboratory of Molecular Genetics of the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH).
Using linkage analysis the team was able to map the gene for this family's deafness to chromosome 5, near another gene causing progressive deafness, DFNA1, recently identified by Dr. Mary Claire King 1. Close inspection of the genetic region revealed, however, that DFNA1 could not be the cause of deafness in this family. It had to be a different gene, which the team named DFNA15. The team found that a gene called POU4F3 was also in the same region of chromosome 5. Examination of the family revealed that the affected family members carried a mutation of the POU4F3 gene. This was especially interesting because the team knew from the work of Allen F. Ryan, Ph.D.2 and associates at the University of California at San Diego that mutations in this gene could cause progressive deafness in mice, an animal model often used for the study of hereditary hearing impairment.
"This gene is particularly interesting because mutations don't inhibit normal auditory development -- the cochlea develops normally and functions normally through childhood and into adulthood," said Robert Morell, Ph.D., a senior staff fellow at NIDCD and one of the authors of the paper. "The changes occur only later in life."
After the family was brought to the attention of Karen B. Avraham, Ph.D., of the Department of Human Genetics, Sackler School of Medicine, Tel Aviv University in Tel Aviv, Israel, she assembled a team that included scientists from the NIH in Bethesda, Maryland; the University of Washington in Seattle, Washington; Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts; and Hadassah University Hospital in Jerusalem, Israel.
"Dr. Avraham and her collaborators have done an outstanding job. Knowledge of the function of this gene could improve understanding of the mechanism underlying progressive nonsyndromic hereditary hearing impairment, possibly including some types of progressive hearing impairment associated with age," commented NIDCD director James F. Battey, Jr., M.D., Ph.D. "The NIDCD is proud to have provided both intramural and extramural support for this research effort which shows the effectiveness of collaborative, team approaches and the judicious use of animal models."
As the nation's focal point for research in human communication, the NIDCD conducts and supports biomedical and behavioral research and research training on normal mechanisms as well as diseases and disorders of hearing, balance, smell, taste, voice, speech and language that affect 46 million Americans.
1 Lynch ED, Lee MK, Morrow JE, Welcsh PL, Leon PE, King MC, Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous. Science, Nov 14, 1997;278(5341):1315-1318.
2 Xiang M, McEvilly RJ, Lou L, Ryan AK, Hooshmand F, O'Connell SM, Keithley EM, Rapaport DH, Ryan AF, Rosenfeld MG, Role of transcription factors BRN-3.1 and BRN-3.2 in auditory and visual system development. Proc. Nat. Acad. Sci.1997,94:9445-9450.
