Mitochondrial cytopathy is characterized by ragged-red muscle fibers (RRF), abnormal mitochondria, and lactic acidosis. This class of diseases is frequently associated with central nervous system, cardiac, kidney, and/or liver dysfunction. Onset occurs in the neonate, infant, child or adult. Heterogeneity of expression occurs within the same pedigree. Oxidative phosphorylation (OXPHOS) proteins are encoded by both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) with resulting Mendalian and maternal modes of inheritance. The grant afford application of the clinical, biochemical, somatic cell genetic, and molecular genetic approaches required to identify the defects responsible for mitochondrial disorders and to subsequently influence their treatment. EBV-transformed lymphocytes from the patient are established and the OXPHOS defect is identified in muscle mitochondria by enzymatic analysis. Cultured lymphocytes and lymphoblasts are screened for altered mitochondrial translation products and for expression of the biochemical defect. Nuclear and cytoplasmic mutations are distinguished by substituting the patient's lymphoblasts mtDNAs with those of a cell with normal OXPHOS (cybrid fusion). The implicated mtDNA genes of cytoplasmic mutants are amplified using the polymerase chain reaction (PCR) and sequenced using the double-stranded dideoxy procedure. Mutant and wild- type oligonucleotide probes are prepared to confirm the mutation and for use in diagnosis. Development of this approach insures long term career growth in the investigation of basic mechanisms of neurologic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08NS001336-01
Application #
3084281
Study Section
Neurological Disorders Program Project Review B Committee (NSPB)
Project Start
1989-07-01
Project End
1994-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Ortiz, R G; Newman, N J; Shoffner, J M et al. (1993) Variable retinal and neurologic manifestations in patients harboring the mitochondrial DNA 8993 mutation. Arch Ophthalmol 111:1525-30
Shoffner, J M; Fernhoff, P M; Krawiecki, N S et al. (1992) Subacute necrotizing encephalopathy: oxidative phosphorylation defects and the ATPase 6 point mutation. Neurology 42:2168-74
Brown, M D; Torroni, A; Shoffner, J M et al. (1992) Mitochondrial tRNA(Thr) mutations and lethal infantile mitochondrial myopathy. Am J Hum Genet 51:446-7
Corral-Debrinski, M; Shoffner, J M; Lott, M T et al. (1992) Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. Mutat Res 275:169-80
Shoffner, J M; Wallace, D C (1992) Heart disease and mitochondrial DNA mutations. Heart Dis Stroke 1:235-41
Corral-Debrinski, M; Stepien, G; Shoffner, J M et al. (1991) Hypoxemia is associated with mitochondrial DNA damage and gene induction. Implications for cardiac disease. JAMA 266:1812-6
Shoffner, J M; Lott, M T; Wallace, D C (1991) MERRF: a model disease for understanding the principles of mitochondrial genetics. Rev Neurol (Paris) 147:431-5
Shoffner, J M; Watts, R L; Juncos, J L et al. (1991) Mitochondrial oxidative phosphorylation defects in Parkinson's disease. Ann Neurol 30:332-9
Shoffner 4th, J M; Wallace, D C (1990) Oxidative phosphorylation diseases. Disorders of two genomes. Adv Hum Genet 19:267-330
Zheng, X X; Shoffner, J M; Voljavec, A S et al. (1990) Evaluation of procedures for assaying oxidative phosphorylation enzyme activities in mitochondrial myopathy muscle biopsies. Biochim Biophys Acta 1019:1-10

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