The mitochondrion is the center stage for energy metabolism, apoptosis, signaling, and ion homeostasis. Much of what we know about this organelle comes from studying mitochondrial respiratory chain disease (RCD). This devastating disease is due to genetic defects in the mtDNA or the nuclear DNA that give rise to a malfunctioning mitochondrial respiratory chain. Virtually all organ systems can be affected. RCD affects an estimated 1:5000 live births and is devastating - it is extremely difficult to diagnose, requiring consultation by multiple physicians and invasive biopsies, and at present no effective therapies are available. A small fraction of these disorders are maternally, but the vast majority of these disorders are due to mutations in nuclear genes, many of which have yet to be identified. Our research team has recently used integrative proteomics to define the ~1100 nuclear genes that encode the mitochondrial proteome - these genes represent a near-comprehensive collection of candidate genes for RCD. In the current application we have assembled a team consisting of leaders in mitochondrial medicine, computational genomics, and large-scale sequencing, to comprehensively resequence all these ~1100 nuclear genes in a panel of ~120 patients with clinically characterized RCD. Through this project, we solve the molecular bases for RCD, establish a facile, comprehensive DNA diagnostic test for RCD;and identify scores of new mitochondrial disease genes that will unlock new pockets of mitochondrial biology.

Public Health Relevance

Mitochondrial disorders comprise one of the largest classes of inherited human disease, affecting both children and adults. We will analyze the DNA of patients with such disorders to discover their molecular basis. The results of this study may help us better diagnose and treat these devastating diseases.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
High Impact Research and Research Infrastructure Programs (RC2)
Project #
3RC2HG005556-01S1
Application #
8099196
Study Section
Special Emphasis Panel (ZHG1-HGR-P (O1))
Program Officer
Wang, Lu
Project Start
2010-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
1
Fiscal Year
2010
Total Cost
$335,592
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Lieber, Daniel S; Hershman, Steven G; Slate, Nancy G et al. (2014) Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency. BMC Med Genet 15:30
Lieber, Daniel S; Calvo, Sarah E; Shanahan, Kristy et al. (2013) Targeted exome sequencing of suspected mitochondrial disorders. Neurology 80:1762-70
Lieber, Daniel S; Vafai, Scott B; Horton, Laura C et al. (2012) Atypical case of Wolfram syndrome revealed through targeted exome sequencing in a patient with suspected mitochondrial disease. BMC Med Genet 13:3