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91.
Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. 总被引:15,自引:0,他引:15
A R Curtis C Fey C M Morris L A Bindoff P G Ince P F Chinnery A Coulthard M J Jackson A P Jackson D P McHale D Hay W A Barker A F Markham D Bates A Curtis J Burn 《Nature genetics》2001,28(4):350-354
We describe here a previously unknown, dominantly inherited, late-onset basal ganglia disease, variably presenting with extrapyramidal features similar to those of Huntington's disease (HD) or parkinsonism. We mapped the disorder, by linkage analysis, to 19q13.3, which contains the gene for ferritin light polypeptide (FTL). We found an adenine insertion at position 460-461 that is predicted to alter carboxy-terminal residues of the gene product. Brain histochemistry disclosed abnormal aggregates of ferritin and iron. Low serum ferritin levels also characterized patients. Ferritin, the main iron storage protein, is composed of 24 subunits of two types (heavy, H and light, L) which form a soluble, hollow sphere. Brain iron deposition increases normally with age, especially in the basal ganglia, and is a suspected causative factor in several neurodegenerative diseases in which it correlates with visible pathology, possibly by its involvement in toxic free-radical reactions. We found the same mutation in five apparently unrelated subjects with similar extrapyramidal symptoms. An abnormality in ferritin strongly indicates a primary function for iron in the pathogenesis of this new disease, for which we propose the name 'neuroferritinopathy'. 相似文献
92.
Paternal origin of new mutations in von Recklinghausen neurofibromatosis 总被引:19,自引:0,他引:19
D Jadayel P Fain M Upadhyaya M A Ponder S M Huson J Carey A Fryer C G Mathew D F Barker B A Ponder 《Nature》1990,343(6258):558-559
Von Recklinghausen neurofibromatosis (NF-1) is a common autosomal dominant disorder. The estimated new mutation rate (1 x 10(-4] is one of the highest for a human disorder. Here we report that in 12 of 14 families we have analysed, the new mutation is of paternal origin. This result is similar to that recently obtained for retinoblastoma. In other genetic disorders that show a bias towards paternal origin of new mutations, there is a marked increase in the incidence of mutations with paternal age, consistent with the mutations arising from replication errors in mitosis of spermatogonial stem cells. In retinoblastoma and NF-1, however, such paternal age effects are slight or absent. The mechanism or timing of germline mutation could therefore be different in the two cases. 相似文献
93.
J H Wolfe M S Sands J E Barker B Gwynn L B Rowe C A Vogler E H Birkenmeier 《Nature》1992,360(6406):749-753
An inherited deficiency of beta-glucuronidase in humans, mice and dogs causes mucopolysaccharidosis VII (Sly syndrome), a progressive degenerative disease that reduces lifespan (to an average of 5 months in mice) and results from lysosomal storage of undegraded glycosaminoglycans in the spleen, liver, kidney, cornea, brain and skeletal system. Bone marrow transplantation in mutant mice provides a source of normal enzyme ('cross-correction'), which substantially improves the clinical condition and extends the average lifespan to 18 months. Gene therapy by transfer of a beta-glucuronidase gene into mutant haematopoietic stem cells is an alternative approach, but it is not known whether the low expression of vector-transferred genes in vivo would be sufficiently effective. Here we show that retroviral vector-mediated transfer of the gene to mutant stem cells results in long-term expression of low levels of beta-glucuronidase which partially corrects the disease by reducing lysosomal storage in liver and spleen. 相似文献
94.
Bonnin A Goeden N Chen K Wilson ML King J Shih JC Blakely RD Deneris ES Levitt P 《Nature》2011,472(7343):347-350
Serotonin (5-hydroxytryptamine or 5-HT) is thought to regulate neurodevelopmental processes through maternal-fetal interactions that have long-term mental health implications. It is thought that beyond fetal 5-HT neurons there are significant maternal contributions to fetal 5-HT during pregnancy but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used Pet1(-/-) (also called Fev) mice in which most dorsal raphe neurons lack 5-HT. We detected previously unknown differences in accumulation of 5-HT between the forebrain and hindbrain during early and late fetal stages, through an exogenous source of 5-HT which is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source. We uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor in both mice and humans. This study reveals a new, direct role for placental metabolic pathways in modulating fetal brain development and indicates that maternal-placental-fetal interactions could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes. 相似文献
95.
We use macroscopic charcoal analysis to reconstruct fire history in sagebrush ( Artemisia tridentata var. wyomingensis and A. tridentata var. tridentate ), in Newark Valley, Nevada. We analyzed charcoal at continuous 1-cm intervals (~7-127 years), and pollen at 2- to 10-cm intervals (~70-263 years) in a core spanning the last 5500 cal yr BP (calendar years before present). A charcoal peak in the historic period was associated with a >1400-ha fire dated to 1986 that burned in the watershed. We reconstructed the prehistoric fire history by inferring fires from similar charcoal peaks that were significantly greater than the background charcoal accumulation. Our results suggest the fire regime is climate and fuel driven. During periods of wetter climate, sagebrush increased and fires were more abundant, and during extended dry periods when sagebrush decreased, fires were less frequent. Our method does not allow calculation of a fire-return interval; however, our results support models that estimate a mean fire-return interval of up to a century in Artemisia tridentata var. wyomingensis . The charcoal record indicates that fires have increased within the historic period. This contrasts with pinyon/juniper studies that indicate an expansion of woodland associated with fewer fires in the historic period. We suggest that in the central Great Basin, a regime of frequent fires in sagebrush that limits woodland expansion is true for the sagebrush-woodland ecotone, but in sagebrush-dominated valleys with lower fuel loads, fires have always been less frequent. Protecting sagebrush-dominated valleys from frequent fire would appear to be consistent with the prehistoric fire regime. 相似文献
96.
97.
All complex life is composed of eukaryotic (nucleated) cells. The eukaryotic cell arose from prokaryotes just once in four billion years, and otherwise prokaryotes show no tendency to evolve greater complexity. Why not? Prokaryotic genome size is constrained by bioenergetics. The endosymbiosis that gave rise to mitochondria restructured the distribution of DNA in relation to bioenergetic membranes, permitting a remarkable 200,000-fold expansion in the number of genes expressed. This vast leap in genomic capacity was strictly dependent on mitochondrial power, and prerequisite to eukaryote complexity: the key innovation en route to multicellular life. 相似文献
98.
Reich D Green RE Kircher M Krause J Patterson N Durand EY Viola B Briggs AW Stenzel U Johnson PL Maricic T Good JM Marques-Bonet T Alkan C Fu Q Mallick S Li H Meyer M Eichler EE Stoneking M Richards M Talamo S Shunkov MV Derevianko AP Hublin JJ Kelso J Slatkin M Pääbo S 《Nature》2010,468(7327):1053-1060
Using DNA extracted from a finger bone found in Denisova Cave in southern Siberia, we have sequenced the genome of an archaic hominin to about 1.9-fold coverage. This individual is from a group that shares a common origin with Neanderthals. This population was not involved in the putative gene flow from Neanderthals into Eurasians; however, the data suggest that it contributed 4-6% of its genetic material to the genomes of present-day Melanesians. We designate this hominin population 'Denisovans' and suggest that it may have been widespread in Asia during the Late Pleistocene epoch. A tooth found in Denisova Cave carries a mitochondrial genome highly similar to that of the finger bone. This tooth shares no derived morphological features with Neanderthals or modern humans, further indicating that Denisovans have an evolutionary history distinct from Neanderthals and modern humans. 相似文献
99.
A M Rosengard H C Krutzsch A Shearn J R Biggs E Barker I M Margulies C R King L A Liotta P S Steeg 《Nature》1989,342(6246):177-180
Tumour metastasis is the principal cause of death for cancer patients. We have identified the nm23 gene, for which RNA levels are reduced in tumour cells of high metastatic potential. In this report we identify the cytoplasmic and nuclear Nm23 protein, and show that it also is differentially expressed in metastatic tumour cells. We also find that the human Nm23 protein has sequence homology over the entire translated region with a recently described developmentally regulated protein in Drosophila, encoded by the abnormal wing discs (awd) gene. Mutations in awd cause abnormal tissue morphology and necrosis and widespread aberrant differentiation in Drosophila, analogous to changes in malignant progression. The metastatic state may therefore be determined by the loss of genes such as nm23/awd which normally regulate development. 相似文献
100.