Defects in the mitochondrial DNA replication enzyme, polymerase γ, are an important cause of mitochondrial disease with ∼25% of all adult diagnoses attributed to mutations in the POLG gene.
Our clustering method provides a powerful tool to predict the pathogenic potential and predicted disease phenotype of novel variants and mutations in POLG, the most common nuclear gene underlying mitochondrial disorders.
Mutations in the DNA polymerase-gamma (POLG) gene are a major cause of clinically heterogeneous mitochondrial diseases, associated with mtDNA depletion and multiple deletions.
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%).
POLG, the gene encoding the catalytic subunit of pol gamma, is a major locus for a wide spectrum of mitochondrial diseases with more than 100 known disease mutations.
(1) Mitochondrial disorders(2) are a well-recognized cause; however, to our knowledge this is the first time that such extensive intracranial calcium deposits have been described in a patient with a POLG1 mutation.
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.
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.
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.
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.
Deficiency of complex II (succinate dehydrogenase, SDH) represents a rare cause of mitochondrial disease and is associated with a wide range of clinical symptoms.
Mice lacking the mitochondrial complex I (CI) subunit Ndufs4 ( Ndufs4<sup>-/-</sup>) develop a fatal progressive encephalopathy and serve as a model for Leigh syndrome, the most common mitochondrial disease in children.
One promising candidate for treatment is the drug rapamycin, which has been shown to extend lifespan in multiple animal models, and which was previously shown to ameliorate mitochondrial disease in a knock-out mouse model lacking a nuclear-encoded gene specifying an OxPhos structural subunit (Ndufs4).
The aim of this multi-site survey was to characterise the natural course of a novel mitochondrial disease with ATP synthase deficiency and mutation in the TMEM70 gene.
In addition to the Björnstad syndrome, BCS1L mutations cause complex III deficiency and the GRACILE syndrome, which in neonates are lethal conditions that have multisystem and neurologic manifestations typifying severe mitochondrial disorders.
Our aim was to assess whether 232A-->G or other BCS1L mutations were present in infants (n = 21) of Finnish origin with severe, lethal disease compatible with mitochondrial disorder.
Our aim was to assess whether 232A-->G or other BCS1L mutations were present in infants (n = 21) of Finnish origin with severe, lethal disease compatible with mitochondrial disorder.