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Improper Use of Modifiers: Not just a Grammatical Error Anymore

Improper Use of Modifiers: Not just a Grammatical Error Anymore

Background: According to Section 28 of Healthy People 2010, genetic mutations are estimated to cause at least half of all cases of inherited or childhood-onset hearing loss. Individual variations in the severity of hearing loss are common and typically attributed to environmental factors and modifier genes – genes that can alter the impact of a mutation in another gene but do not by themselves cause hearing loss. Modifier genes in the genetic background of an individual can affect the severity of hearing loss caused by a mutation.

Schematic secondary structure of cadherin-23 and mutations in the waltzer mouse mutant.

Schematic structure of cadherin 23.

Advance: NIDCD-supported scientists have identified a genetic variation in humans that affects the severity of hearing loss caused by a mutation of another gene. In a study of a single large family, five adult siblings had a mutant form of the gene that encodes for the protein, cadherin 23, which is required for regulating the amount of calcium both around and within sensory hair cells. Calcium is important for hair cell structure and nerve impulse transduction. However, the degree of hearing loss among the siblings varied. While three of the five individuals had severe to profound deafness, the other two had hearing loss only in the higher frequencies. This variability suggested the action of a modifier gene.

Implications: Clinical genetic testing for modifier genes would provide valuable information for predicting the severity and progression of hearing loss associated with advanced age, exposure to loud noise, and mutations in other deafness genes. Understanding how modifier genes work would also provide a critical entry point for the design and testing of biological interventions to modify the severity of hearing loss. For example, since calcium pumps are excellent targets for drug development, this discovery reveals an opportunity to devise and test potential therapies to prevent or slow progressive hearing loss.

Citation: Schultz JM, Yang Y, Caride AJ, Filoteo AG, Penheiter AR, Lagziel A, Morell RJ, Mohiddin SA, Fananapazir L, Madeo AC, Penniston JT, Griffith AJ, Modification of human hearing loss by plasma-membrane calcium pump PMCA2. NEJM 352: 1557-1564, 2005.

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