David Dimmock, MD Assistant Professor, Pediatrics Specialization: Genetics Tel: (414) 456-4452 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.
There are few good models of hepatic mitochondrial disease, specifically mouse models fail to recapitulate human disease. We are therefore developing a tissue culture based approach to study the underlying pathophysiology of mitochondrial DNA depletion in human derived hepatocytes.
Acute Liver Failure in childhood is etiologically heterogeneous with the PALF study showing 50% of children had no known cause of their acute liver failure. Our preliminary data has shown that acute liver failure is a common problem in mtDNA depletion syndromes. Indeed, some patients with milder mutations may only experience isolated liver failure following environmental triggers. Therefore, we are evaluating the role of mutations in genes know to cause primary mtDNA depletion in patients with isolated acute liver failure.
We have significant experience in our laboratory of translating research tools into clinical testing. WE are currently focusing on evaluating strategies to facilitate the transition of high throughput sequencing and tissue based testing into the clinic.
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