We sequenced the exons and flanking intron region from approximately 350 patients displaying a phenotype consistent with POLG related mitochondrial disease and found informative mutations in 61 (17%).
A POLGY955C point mutation causes human chronic progressive external ophthalmoplegia (CPEO), a mitochondrial disease with eye muscle weakness and mtDNA defects.
Molecular studies in the POLG gene should be addressed in patients with mitochondrial disease, particularly in those with PEO, and multiple mtDNA deletions.
Molecular studies in the POLG gene should be addressed in patients with mitochondrial disease, particularly in those with PEO, and multiple mtDNA deletions.
We conclude that mtDNA point mutations do not appear to be directly or indirectly involved in the pathogenesis of mitochondrial disease in patients with different POLG1 mutations.
Progressive external ophthalmoplegia (PEO) is a mitochondrial disorder associated with mutations in the POLG gene encoding the mitochondrial DNA polymerase (pol gamma).
Our findings suggest that the presence of HOD, in the appropriate clinical setting, should alert the clinician to the possibility of a mitochondrial disorder and the need to screen for mutations in POLG and SURF1 genes.
One potentially fruitful therapeutic approach for this mitochondrial disorder should be considered the production of human recombinant full length L-Sco2 protein and its deliberate transduction into the mitochondria.
Mutations in the nuclear SURF-1 gene lead directly to cytochrome-c oxidase deficiency, the most common respiratory chain defect in Leigh syndrome, a neurodegenerative mitochondrial disease involving the deep gray matter and brain stem.
This review summarizes recent developments, including our efforts in elucidation of the molecular basis of human mitochondrial diseases due to specific defects of COX with special focus on SURF1 assembly protein.
A greater understanding of the pathophysiology of a number of nuclear genetic mitochondrial disorders suggests new avenues for treatment (such as copper-histidine in children with SCO2 gene mutations, and strategies modifying intra-mitochondrial nucleoside pools in the various disorders of mtDNA maintenance).
Sequence analysis of SURF-1 revealed mutations in numerous DNA samples from LD(COX-) patients, indicating that this gene is responsible for the major complementation group in this important mitochondrial disorder.
SDH defects are associated with mitochondrial disorders and risk for various cancers; immunochemical analysis indicated loss of SDHB protein expression in the patient's tumor, compatible with SDH deficiency.
Of the 34 patients with mitochondrial abnormalities on skin biopsy, 20 also had muscle biopsies performed and nine showed abnormalities suggestive of a mitochondrial disorder including absent cytochrome oxidase staining (n=2), increased subsarcolemmal NADH, SDH, or cytochrome oxidase staining (n=1), or ultrastructural findings including large mitochondrial size (n=5), abnormal mitochondrial structure (n=5), and increased mitochondrial number (n=4).