Modifier locus for mitochondrial DNA disease: Linkage and linkage disequilibrium mapping of a nuclear modifier gene for maternally inherited deafness

Purpose: To examine the role of the nuclear genome in affecting the phenotypic expression of the simplest model of a mitochondrial DNA disease, maternally transmitted deafness. Methods: Linkage analysis in families with maternally inherited deafness associated with the homoplasmic A1555G mutation. Results: Significant linkage and linkage disequilibrium on chromosome 8 was identified. Conclusions: This finding represents the first identification of a modifier locus for a human mitochondrial DNA disease and supports the concept of mitochondrial DNA diseases having complex genetic inheritance. The eventual identification of this modifier gene will provide insights into the pathophysiological pathways determining the clinical expression of mitochondrial DNA diseases, an important step toward diagnostic and therapeutic interventions.