Progressive external ophthalmoplegia: a new family with tremor and peripheral neuropathy. Am J Med Genet A

American Journal of Medical Genetics Part A (Impact Factor: 2.16). 06/2005; 135(2):217-9. DOI: 10.1002/ajmg.a.30672
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    • "A further consideration emerges from the evidence of an additional association between the POLG p.A899T variant and SANDO syndrome. The p.A899T has initially been described in compound heterozygosity [13,14] and frequently associated with the clinical triad of sensory ataxic, ptosis, and PEO together with a mood disorder and a movement disorder such as Dopamine-agonist responsive parkinsonism. In the face of an ever increasing, pleiomorphic array of features associated with mutations in POLG[15], identification of apparent mutation-specific clinical characteristics might facilitate molecular confirmation in complex patients, prevent possible co-morbidities, and permit to adopt effective symptomatic therapies. "
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    ABSTRACT: Disorders of oxidative phosphorylation affects 1/5000 individuals and present heterogeneous involvement of tissues highly dependent upon ATP production. Here we present the case of a 48-year-old woman carrying a homozygous mutation (p.A899T) in mitochondrial polymerase gamma (POLG) and manifesting with a complex neurological phenotype including Dopamine-agonist responsive Parkinsonism. This case report is further evidence that mitochondrial dysfunction might play a role in Parkinson's Disease pathogenesis and helps in identification of apparent mutation-specific clinical characteristics. Mutations in POLG should be looked for in cases of Parkinsonism, especially when multisystem neurological involvement is found.
    BMC Medical Genetics 10/2013; 14(1):105. DOI:10.1186/1471-2350-14-105 · 2.08 Impact Factor
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    • "(iii) Dominance/recessivity of mutations whose inheritance is unclear, due to the lack of family records, can be better defined by using yeast heteroallelic strains, containing both the mutant mip1 allele and the wild-type MIP1, thus mimicking the human diploid condition. For instance, the A889T mutation was shown to be slightly dominant in yeast, in agreement with the hypothesis that penetrance of the phenotype and development of pathology are influenced by other genetic or environmental factors (Hisama et al., 2005). Also, studies in vivo showed that the E1143G mutation is not a neutral SNP in S. cerevisiae, but it rather acts as a cis-modulator of Mip1 activity, in agreement with in vitro studies on human POLG variants (Chan et al., 2006). "
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    ABSTRACT: The yeast Saccharomyces cerevisiae was used to validate the pathogenic significance of eight human mutations in the gene encoding for the mitochondrial DNA polymerase gamma, namely G303R, S305R, R386H, R574W, P625R, D930N, K947R and P1073L, among which three are novel and four are of unclear pathological significance. Mitochondrial DNA extended and point mutability as well as dominance/recessivity of each mutation has been evaluated. The analysis in yeast revealed that two mutations, S305R and R386H, cannot be the sole cause of pathology observed in patients. These data led us to search for a second mutation in compound with S305R and we found a mutation, P1073L, missed in the first genetic analysis. Finally, a significant rescue of extended mutability has been observed for several dominant mutations by treatment with mitochondrial antioxidants.
    Mitochondrion 09/2010; 11(1):182-90. DOI:10.1016/j.mito.2010.09.007 · 3.25 Impact Factor
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    • "Yeast models have also been constructed of several human mutations alone or in combination, among which G848S-E1143G and H932Y- G1051R associated in trans, and A889T-E1143G associated in cis (Baruffini et al., 2007; Spinazzola et al., 2009; Stricker et al., 2009). The mutation A889T is slightly dominant in yeast, in agreement with the hypothesis that the gene penetrance is influenced by other genetic or environmental factors (Hisama et al., 2005). Furthermore, in vivo studies in yeast have shown that the mutation E1143G is not a neutral SNP (Baruffini et al., 2007), but rather acts as a cis-modulator of Mip1 activity, in agreement with the observation that in vitro E1143G was somewhat detrimental to protein stability (Chan et al., 2006). "
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    ABSTRACT: Nowadays, mitochondrial diseases are recognized and studied with much attention and they cannot be considered anymore as 'rare diseases'. Yeast has been an instrumental organism to understand the genetic and molecular aspects of the many roles of mitochondria within the cells. Thanks to the general conservation of mitochondrial genes and pathways between human and yeast, it can also be used to model some diseases. In this review, we focus on the most recent topics, exemplifying those for which yeast models have been especially valuable.
    FEMS Yeast Research 09/2010; 10(8):1006-22. DOI:10.1111/j.1567-1364.2010.00685.x · 2.82 Impact Factor
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