A novel SLC26A4 (PDS) deafness mutation retained in the endoplasmic reticulum

Objectives: To identify mutations in the SLC26A4 gene in individuals with nonsyndromic hearing loss and enlarged vestibular aqueduct, to design a predicted model of the pendrin protein, and to characterize novel mutations by means of localization in mammalian cells and effect of the mutation on the predicted model. Design: Validation of the mutation by its exclusion in more than 300 individuals with normal hearing. Setting: A laboratory of genetics of hearing loss research, clinical genetics laboratories, an otolaryngology department at Tel Aviv University, and medical centers in Israel. Patients: A patient with nonsyndromic hearing loss and enlarged vestibular aqueduct, 203 deaf probands, and 310 controls with normal hearing. Interventions: Sequencing the SLC26A4 gene in the patient with nonsyndromic hearing loss and enlarged vestibular aqueduct. Transfection of yellow fluorescent protein (YFP) constructs into mammalian COS7 cells. Designing a computational model of the human SLC26A4 protein. Main Outcome Measure: Detection of a novel c.1458_1459insT SLC26A4 mutation. Results: A computational model of the human pendrin protein suggests that the novel c.1458_1459insT mutation leads to a prematurely truncated protein, p.Ile487TyrfsX39. Mammalian COS7 cells transfected with the YFP-1458_1459insT construct showed mislocalization of the mutant protein. Conclusions: A novel SLC26A4 mutation was detected in Israel. Because current estimates demonstrate that SLC26A4 mutations are involved in up to 4% of nonsyndromic deafness, our findings emphasize the importance of adding a molecular test for the SLC26A4 gene in the diagnosis of deafness, particularly when bone abnormalities are involved, to the list of genes screened in Israel and elsewhere in the world.