Abstract 2818: Nuclear-Mitochondrial DNA Interaction Causing Cardiomyopathy
In two unrelated families, hypertrophic cardiomyopathy (HCM) was associated with a homoplasmic A4300G mutation in the tRNAIle gene of the mitochondrial DNA (mtDNA) in all affected and unaffected maternal relatives. Biochemical and histochemical analysis showed severely decreased respiratory chain activity, and very low steady-state levels of the tRNAIle in the heart, in support of the pathogenic role of the mtDNA mutation. Cybrids containing the A4300G mutation in a neutral background of the mtDNA-less (ρ0) 143B cells, had normal respiratory chain activity, indicating that the patient’s nuclear genome may play a role in the expression of the phenotype. However, the primary fibroblast and myoblast cultures did not reveal any defects. Expression of the phenotype was isolated to the heart tissue, indicating tissue-specificity. To confirm this, we analyzed cardiomyocyte (CM) cultures with normal and with patient nucleus, in combination with wild type (WT) and patient (A4300G) mitochondria. The results are as shown in the table⇓. COX activity is normal in normal CM (AC16), and in cells with normal CM nucleus and 4300 mitochondria. In the patient’s CMs, which contain the patient nucleus and 4300 mitochondria, COX activity is low. However, in cells with the patient nucleus and normal mitochondria, the COX activity is normal. These results clearly indicate that both the patient’s nucleus and the patient’s mitochondria are essential for the expression of the COX deficiency in CMs.
Conclusion: Segregation of the maternally inherited mtDNA mutation with respiratory chain deficiency indicates that it may the primary mutation, necessary for the expression of the phenotype, but not sufficient to be pathogenic in the absence of the patient’s nucleus. We present evidence for a tissue specific nuclear modifier gene, which may act synergistically with the mtDNA mutation to cause a tissue specific phenotype.