Alpers Syndrome is a classic neurogenetic disease first described by Bernard Alpers in 1931. Our group recently defined the molecular basis of this fatal disease of brain and liver. It is characterized by mutations in the catalytic subunit of the mitochondrial DNA polymerase gamma (POLG). These mutations lead to a progressive mitochondrial DNA depletion disorder that is tissue and age-dependent, and are predicted to have effects on the DNA repair function of POLG as well. The combination of enzymatic defects is associated with late-onset mitochondrial DNA (mtDNA) depletion and failure of oxidative phosphorylation. However, early in the course of disease, at the onset of symptoms, mtDNA depletion and respiratory enzyme deficiency are not present, and cannot be used to confirm the diagnosis. POLG protein is known to play 2 roles in the cell. The first is mtDNA replication. The second function is associated with the deoxyribose phosphate (dRP) lyase activity of POLG, and plays an important role in base excision repair (BER). In the proposed research we will test the Hypothesis that early in the course of Alpers Syndrome, symptoms result from a failure in mitochondrial BER, and that damaged mtDNA accumulates before mtDNA depletion is observed.
The Specific Aims of this project are: 1. Construct a mouse model of Alpers Syndrome homozygous for the mouse equivalent of the A467T substitution in the mitochondrial DNA polymerase gamma (POLG) 2. Measure the developmental and tissue-specific rate of mtDNA damage and depletion 3. Study the relationship between mtDNA damage, depletion, POLG content, oxphos capacity, and tissue- specific disease phenotype ? ? ?
| Wong, Lee-Jun C; Naviaux, Robert K; Brunetti-Pierri, Nicola et al. (2008) Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat 29:E150-72 |
