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New 'Deafness' Gene Causes Two Forms of Hearing Loss
A newly discovered gene is the source of two forms of deafness in both mice and humans, says a study appearing in the March 1, 2002, issue of Nature Genetics. Researchers in the Laboratory of Molecular Genetics of the National Institute on Deafness and Other Communication Disorders (NIDCD), Bethesda, Md., in collaboration with 21 other scientists, have found that mutations of TMC1, a newly identified gene located on chromosome 9 in humans, and chromosome 19 in mice, can cause both dominant and recessive forms of nonsyndromic hearing loss.
Nonsyndromic hearing loss accounts for approximately two-thirds of all hereditary hearing loss, with approximately 70-80 percent of the cases inherited in a recessive pattern and 15-20 percent in a dominant pattern. The term “nonsyndromic” refers to isolated hearing loss that is not associated with other inherited characteristics, such as the changes in skin or hair pigmentation exhibited by people with Waardenburg syndrome. One type of dominant hearing loss, named DFNA36 to distinguish it from other forms of dominant hearing loss associated with different genes, is expressed when only one parent passes an altered or mutated copy of TMC1 to an offspring. DFNA36 deafness results in normal hearing in early childhood, but rapidly progresses to profound deafness by the third decade of life. A recessive form of deafness, named DFNB7/B11, occurs when both parents transmit mutated copies of TMC1 to their affected offspring, causing severe to profound deafness at birth. Carriers of only one recessive mutation of TMC1 have normal hearing, however.
TMC1, which is the abbreviated name for transmembrane cochlear-expressed gene 1, is thought to play a role in the functioning of cochlear hair cells, which convert sound vibrations into electrical signals that travel to the brain. Researchers were able to identify TMC1 by conducting gene mapping studies of a large North American family with DFNA36 deafness and 11 unrelated families from Pakistan and India with DFNB7/B11 deafness. They found that the location of the gene that causes DFNA36 deafness overlapped with the DFNB7/B11 gene location on chromosome 9, suggesting that these two forms of deafness may be caused by different mutations of the same gene. TMC1 was located in the region of overlap. In all 12 families, one of eight different TMC1 mutations was responsible for the hearing loss.
In mice, Tmc1 (lowercased for mice) is located on chromosome 19 in a region known to give rise to a mutation (called deafness) that causes recessive deafness. Analysis of the Tmc1 nucleotide sequence in deafness mice revealed the deletion of exon 14, which is required for the proper coding and production of Tmc1 protein. Deafness mice are profoundly deaf, and the cochlear hair cells show no electrical response to sound stimulation. That observation, combined with the knowledge that the Tmc1 gene is expressed, or “turned on,” in cochlear hair cells, indicates that Tmc1, as well as TMC1, is required for normal cochlear hair cell function.
The study was a collaborative effort of the NIDCD with scientists representing Punjab University, Lahore, Pakistan; Louisiana State University, New Orleans, La.; All-India Institute of Medical Sciences, New Delhi, India; Rotary Deaf School, Maharashtra, India; New York School of Medicine, New York, N.Y.; Tulane University, New Orleans; and the National Institute of Neurological Disorders and Stroke, Bethesda, Md. As the nation’s focal point for research in human communication, the NIDCD supports and conducts research and research training on normal mechanisms as well as diseases and disorders of hearing, balance, smell, taste, voice, speech and language that affect millions of Americans.