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A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging.

ABSTRACT: The inherent complex and pleiotropic phenotype of mitochondrial diseases poses a significant diagnostic challenge for clinicians as well as an analytical barrier for scientists. To overcome these obstacles we compiled a novel database, www.mitodb.com, containing the clinical features of primary mitochondrial diseases. Based on this we developed a number of qualitative and quantitative measures, enabling us to determine whether a disorder can be characterized as mitochondrial. These included a clustering algorithm, a disease network, a mitochondrial barcode and two scoring algorithms. Using these tools we detected mitochondrial involvement in a number of diseases not previously recorded as mitochondrial. As a proof of principle Cockayne syndrome, ataxia with oculomotor apraxia 1 (AOA1), spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) and ataxia-telangiectasia have recently been shown to have mitochondrial dysfunction and those diseases showed strong association with mitochondrial disorders. We next evaluated mitochondrial involvement in aging and detected two distinct categories of accelerated aging disorders, one of them being associated with mitochondrial dysfunction. Normal aging seemed to associate stronger with the mitochondrial diseases than the non-mitochondrial partially supporting a mitochondrial theory of aging.

SUBMITTER: Scheibye-Knudsen M

PROVIDER: S-EPMC3629291 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging.

Scheibye-Knudsen Morten M Scheibye-Alsing Karsten K Canugovi Chandrika C Croteau Deborah L DL Bohr Vilhelm A VA

Aging 20130301 3

The inherent complex and pleiotropic phenotype of mitochondrial diseases poses a significant diagnostic challenge for clinicians as well as an analytical barrier for scientists. To overcome these obstacles we compiled a novel database, www.mitodb.com, containing the clinical features of primary mitochondrial diseases. Based on this we developed a number of qualitative and quantitative measures, enabling us to determine whether a disorder can be characterized as mitochondrial. These included a cl ...[more]

PMID: 23524341

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Project description:BackgroundAlthough many diseases have been well characterized at the molecular level, the underlying mechanisms are often unknown. Nearly half of all human genes remain poorly studied, yet these genes may contribute to a number of disease processes. Genes involved in common biological processes and diseases are often co-expressed. Using known disease-associated genes in a co-expression analysis may help identify and prioritize novel candidate genes for further study.ResultsWe have created an online tool, called GeneFriends, which identifies co-expressed genes in over 1,000 mouse microarray datasets. GeneFriends can be used to assign putative functions to poorly studied genes. Using a seed list of disease-associated genes and a guilt-by-association method, GeneFriends allows users to quickly identify novel genes and transcription factors associated with a disease or process. We tested GeneFriends using seed lists for aging, cancer, and mitochondrial complex I disease. We identified several candidate genes that have previously been predicted as relevant targets. Some of the genes identified are already being tested in clinical trials, indicating the effectiveness of this approach. Co-expressed transcription factors were investigated, identifying C/ebp genes as candidate regulators of aging. Furthermore, several novel candidate genes, that may be suitable for experimental or clinical follow-up, were identified. Two of the novel candidates of unknown function that were co-expressed with cancer-associated genes were selected for experimental validation. Knock-down of their human homologs (C1ORF112 and C12ORF48) in HeLa cells slowed growth, indicating that these genes of unknown function, identified by GeneFriends, may be involved in cancer.ConclusionsGeneFriends is a resource for biologists to identify and prioritize novel candidate genes involved in biological processes and complex diseases. It is an intuitive online resource that will help drive experimentation. GeneFriends is available online at: http://genefriends.org/.

Dataset Information

A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging.

Publications

A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging.

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