IDENTIFIYNG THE MOLECULAR GENETIC BASIS OF HUMAN COENZYME Q10 DEFICIENCY, A TREATABLE CAUSE OF HEREDITARY ATAXIA

Mitochondria are often called the –powerhouses of the cells” because they generate most of the cellês energy. Defects of mitochondria cause diverse human diseases. A subtype of mitochondrial disease is caused by deficiency of coenzyme Q10 (CoQ10), an essential component of the mitochondria involved in energy production. Primary CoQ10 deficiency may be a common cause of childood incoordination called cerebellar ataxia and is thought to be caused by mutations in the genetic material (chromosomes) stored in the nucleus of the cell. In addition, patients often have muscle weakness, epilepsy, slow development in childood, mental retardation, and other neurological problems. Patients often improve dramatically with CoQ10 supplementation. The aim of our proposal is to identify the genetic cause of this disease, which will allow accurate diagnosis of CoQ10 deficiency, Identification of CoQ10 deficient patients is particularly important because they benefit substantially from CoQ10 therapy. We have linked the cause of the disease to a region of chromosome 9 in a family with 4 affected individuals. We are attempting to restrict the size of the linked region in order to reduce the number of candidate genes. If we cannot narrow down the linked region because of the small number of available patients, we may attempt to identify the mutated gene by studying patientsê cells. We are growing skin cells (fibroblasts) from patients and normal individuals. The patientsê fibroblasts have less CoQ10 than normal cells. By introducing chromosome 9 from a normal individual into the patientsê fibroblast we expected to increase the cellês CoQ10 level to normal. If this –complementation” experiment works, we will transfer pieces of chromosome 9 into the patientsê fibroblasts to narrow down the linked region and ultimately identify the mutation causing the disease.After identifying the responsible gene, we will study other patients with the same disease because it is possible that different fa