David Dimmock, MD Assistant Professor, Pediatrics Specialization: Genetics Tel: (414) 456-4462 Dr. Dimmock's CV Email Dr. Dimmock
Primary mitochondrial DNA (mtDNA) depletion is caused by mutations in genes involved in the synthesis of mitochondrial nucleotides or genes involved in the maintenance of the mitochondrial genome. Definitive diagnosis is established by finding mutations in any one of the 9 genes currently know to lead to this disorder. However a recent large study could identify 2 causal mutations in only 20% of patients with multisystemic mtDNA depletion. This suggests that there are other as yet undescribed genes that lead to mtDNA depletion. Our lab is therefore utilizing linkage analysis and high throughput sequencing of candidate genes to discover novel genes involved in primary mtDNA depletion. Further expansion of this technology is expected to enable genomic level screening for a variety of other disorders.
We have demonstrated that mtDNA depletion is seen in a significant proportion of children with liver failure and cholestasis however causality has yet to be established. Therefore, we are evaluating patients for mutations in primary mtDNA depletion and developing models to explore the pathophysiology.
There are few good models of hepatic mitochondrial disease, specifically current “knock out” mouse models fail to recapitulate human disease. This likely because of the genes targeted for knock out. We are therefore analyzing a knock out rat model of a mitochondrial hepatic disease. Our other model is human derived cultures in which we can manipulate conditions more rapidly to study the underlying disease mechanism of mitochondrial DNA depletion and evaluate specific rescue therapies
In the future we aim to translate tissue culture based rescue into a whole organism therapy providing a potential treatment strategy for this group of disorders.
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