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PubMed2026

Twelve Japanese patients with POLG-related disorders: Population-specific genetic differences of POLG variants in Japan and Europe.

BACKGROUND: POLG encodes mitochondrial DNA (mtDNA) polymerase γ. Pathogenic POLG variants cause mitochondrial diseases, including progressive external ophthalmoplegia. POLG-related disorders are relatively common in Europe, possibly because of the high prevalence of carriers in the general population, but remain rare in Japan for unclear reasons. METHODS: We performed long-range PCR on mtDNA from skeletal muscle and/or peripheral blood from 3146 patients with suspected mitochondrial disease between 1993 and 2021. We selected 167 individuals with clinical features suggestive of POLG-related disorders for POLG gene analysis; all lacked pathogenic mtDNA point mutations, and most had multiple mtDNA deletions and/or a family history of mitochondrial disease. RESULTS: Among the 167 patients (median age: 52 years, range: 0-83 years, 11% pediatric cases), we identified 12 Japanese patients with POLG-related disorders and six POLG variants, including one novel variant. The six variants were p.Y955C, p.R943H, p.T599I, p.M299L, p.Y1210* (c.3626_3629dupGATA), and the novel variant p.F377S (c.1130T>C). Neither these six variants nor the 10 previously reported cases from Japan included the POLG variants that are more frequent in Europe. We also analyzed three population databases: two whole-genome sequencing databases covering 61,000 and 9850 Japanese individuals, respectively, and one global population database (gnomAD) covering 730,000 individuals worldwide. POLG variants that are more frequent in Europe were not detected in the Japanese databases or among East Asian individuals in gnomAD. CONCLUSIONS: Our findings suggest population-specific genetic differences in POLG between Japanese and European populations, explaining the lower frequency of POLG-related disorders in Japan.

CPEO↗

PubMed2025

Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants.

PURPOSE: Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the MitoPhen database to characterize phenotypic variation across PMD more systematically. METHODS: Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce MitoPhen v2. Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes. RESULTS: MitoPhen v2 adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using MT-TL1, single large-scale mitochondrial DNA deletions, and POLG as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without. CONCLUSION: MitoPhen v2 enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.

Humans↗

PubMed1988

Human gene expression first occurs between the four- and eight-cell stages of preimplantation development.

The earliest stages of development in most animals, including the few mammalian species that have been investigated, are regulated by maternally inherited information. Dependence on expression of the embryonic genome cannot be detected until the mid two-cell stage in the mouse, the four-cell stage in the pig (J. Osborn & C. Polge, personal communication), and the eight-cell stage in the sheep. Information about the timing of activation of the embryonic genome in the human is of relevance not only to the therapeutic practice of in vitro fertilization and embryo transfer (IVF), but more importantly for the successful development of techniques for the preimplantation diagnosis of certain inherited genetic diseases. We describe here changes in the pattern of polypeptides synthesized during the pre-implantation stages of human development, and demonstrate that some of the major qualitative changes which occur between the four- and eight-cell stages are dependent on transcription. In addition, it appears that cleavage is not sensitive to transcriptional inhibition until after the four-cell stage.

Amanitins↗

PubMed1987

Biochemical and functional aspects of recovery of mammalian systems from deep sub-zero temperatures.

The viability of isolated mammalian systems is, apart from possible morphological changes, essentially conditioned by the biochemical modifications from normal physiological conditions to an artificial environment where blood supply is interrupted leading to ischaemia and where the temperature is lowered. In order to survive freezing and thawing, mammalian systems have to be protected by cryoprotectants, which apart from some inherent toxicity, may also interact with vital metabolic mechanisms (Conover, 1969, 1975: Fahy, 1986: Fahy et al. 1984: Jacobs & Herschler, 1986: Karow, 1982: Penninckx et al. 198 3: Polge et al. 1949: Rowe et al. 1980: Schlafer, 1981: Taylor & Pignat, 1982). Cellular volume changes as a result of modifications in extra- a and intracellular osmolality occurring during freezing and thawing prove particularly detrimental to the normal functioning of the cellular membranes (Crowe et al. 1983: Farrant, 1980: Farrant et al. 1977b: Karow, 198 2: Mazur & Rigopoulos, 1983: Meryman, 1970: Meryman et al. 1977: Nei, 19 76: Santarius & Giersch, 1983). Furthermore intracellular ice formation enhances structural and metabolic injury to subcellular particles(Farrant et al. 1977a: Fink, 1986: Fishb ein & Griffin, 1976: Fujikawa, 1981: Fuller & De Loecker, 1985: Lazarus et al. 1982: Malinin, 1972: Mazur, 1984: Pavlock et al. 1984:Penninckx et al. 1984: Persidsky & Ellet, 1971: Rubinacci et al. 1986: Shikama, 1965: Steponkus & Wiest, 1979: Strauss & Ingenito, 1980: Takehara & Rowe, 1971: Tamiya et al. 1985). Even with the protection of structural integrity, the preservation of energy production and the maintenance of the specific intracellular medium are essential to secure viability (Pegg, 1981).

Animals↗

PubMedDate not supplied

The freezing of mammalian embryos: perspectives and possibilities.

Since the Ciba Foundation Symposium in 1952 on Mammalian Germ Cells when Dr Audrey Smith reported that 'exposure to very low temperatures is not incompatible with further development of mammalian eggs', much progress has been made on the problem of freezing mammalian embryos. The significant steps leading to this progress are reviewed and an attempt is made to assess the extent of our current knowledge and to relate this to experience gained in other fields of low temperature biology. There is good evidence that certain basic principles concerning cooling and warming rates are applicable to the preservation of all mammalian embryos so far studied, but differences between species and between stages of development within species exist, particularly in their resistance to cooling in temperature ranges above 0 degrees C. Some of these differences are illustrated by reference to experiments with pig embryos. Clearly there are many problems remaining to be solved, but practical applications of techniques for long-term storage of mammalian embryos are already feasible and offer interesting possibilities for future development.

Cryoprotective Agents↗

PubMed1971