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861.
Stewart SA Ben-Porath I Carey VJ O'Connor BF Hahn WC Weinberg RA 《Nature genetics》2003,33(4):492-496
Cultured primary human cells inevitably enter a state of replicative senescence for which the specific molecular trigger is unknown. We show that the single-strand telomeric overhang, a key component of telomere structure, is eroded at senescence. Expression of telomerase prevents overhang loss, suggesting that this enzyme prevents senescence by maintaining proper telomere structure. In contrast, progressive overhang loss occurs in cells that avoid senescence through the inactivation of p53 and Rb, indicating that overhang erosion is the result of continuous cell division and not a consequence of senescence. We thus provide evidence for a specific molecular alteration in telomere structure at senescence and suggest that this change, rather than overall telomere length, serves to trigger this state. 相似文献
862.
Gibbons RJ Pellagatti A Garrick D Wood WG Malik N Ayyub H Langford C Boultwood J Wainscoat JS Higgs DR 《Nature genetics》2003,34(4):446-449
Inherited mutations of specific genes have elucidated the normal roles of the proteins they encode by relating specific mutations to particular phenotypes. But many potentially informative mutations in such genes are lethal early in development. Consequently, inherited mutations may not reflect all the functional roles of such proteins. Acquired, somatic defects should reflect a wider spectrum of mutations because they are not prone to negative selection in development. It has been difficult to identify such mutations so far, but microarray analysis provides a new opportunity to do so. Using this approach, we have shown that in individuals with myelodysplasia associated with alpha-thalassemia (ATMDS), somatic mutations of the gene encoding the chromatin remodeling factor ATRX cause an unexpectedly severe hematological phenotype compared with the wide spectrum of inherited mutations affecting this gene. These findings cast new light on this pleiotropic cofactor, which appears to be an essential component rather than a mere facilitator of globin gene expression. 相似文献
863.
864.
865.
The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes 总被引:2,自引:0,他引:2
Skaletsky H Kuroda-Kawaguchi T Minx PJ Cordum HS Hillier L Brown LG Repping S Pyntikova T Ali J Bieri T Chinwalla A Delehaunty A Delehaunty K Du H Fewell G Fulton L Fulton R Graves T Hou SF Latrielle P Leonard S Mardis E Maupin R McPherson J Miner T Nash W Nguyen C Ozersky P Pepin K Rock S Rohlfing T Scott K Schultz B Strong C Tin-Wollam A Yang SP Waterston RH Wilson RK Rozen S Page DC 《Nature》2003,423(6942):825-837
866.
Stratigraphic,chronological and behavioural contexts of Pleistocene Homo sapiens from Middle Awash,Ethiopia 总被引:4,自引:0,他引:4
Clark JD Beyene Y WoldeGabriel G Hart WK Renne PR Gilbert H Defleur A Suwa G Katoh S Ludwig KR Boisserie JR Asfaw B White TD 《Nature》2003,423(6941):747-752
Clarifying the geographic, environmental and behavioural contexts in which the emergence of anatomically modern Homo sapiens occurred has proved difficult, particularly because Africa lacked adequate geochronological, palaeontological and archaeological evidence. The discovery of anatomically modern Homo sapiens fossils at Herto, Ethiopia, changes this. Here we report on stratigraphically associated Late Middle Pleistocene artefacts and fossils from fluvial and lake margin sandstones of the Upper Herto Member of the Bouri Formation, Middle Awash, Afar Rift, Ethiopia. The fossils and artefacts are dated between 160,000 and 154,000 years ago by precise age determinations using the 40Ar/39Ar method. The archaeological assemblages contain elements of both Acheulean and Middle Stone Age technocomplexes. Associated faunal remains indicate repeated, systematic butchery of hippopotamus carcasses. Contemporary adult and juvenile Homo sapiens fossil crania manifest bone modifications indicative of deliberate mortuary practices. 相似文献
867.
868.
869.
X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling 总被引:19,自引:0,他引:19
Döffinger R Smahi A Bessia C Geissmann F Feinberg J Durandy A Bodemer C Kenwrick S Dupuis-Girod S Blanche S Wood P Rabia SH Headon DJ Overbeek PA Le Deist F Holland SM Belani K Kumararatne DS Fischer A Shapiro R Conley ME Reimund E Kalhoff H Abinun M Munnich A Israël A Courtois G Casanova JL 《Nature genetics》2001,27(3):277-285
The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds, and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding region of IKBKG are associated with EDA-ID, and stop codon mutations, with OL-EDA-ID. IKBKG encodes NEMO, the regulatory subunit of the IKK (IkappaB kinase) complex, which is essential for NF-kappaB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses. We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling. We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling. Finally, we show that abnormal immunity in OL-EDA-ID patients results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1beta, IL-18, TNFalpha and CD154. We thus report for the first time that impaired but not abolished NF-kappaB signaling in humans results in two related syndromes that associate specific developmental and immunological defects. 相似文献
870.
Rampoldi L Dobson-Stone C Rubio JP Danek A Chalmers RM Wood NW Verellen C Ferrer X Malandrini A Fabrizi GM Brown R Vance J Pericak-Vance M Rudolf G Carrè S Alonso E Manfredi M Németh AH Monaco AP 《Nature genetics》2001,28(2):119-120
Chorea-acanthocytosis (CHAC, MIM 200150) is an autosomal recessive neurodegenerative disorder characterized by the gradual onset of hyperkinetic movements and abnormal erythrocyte morphology (acanthocytosis). Neurological findings closely resemble those observed in Huntington disease. We identified a gene in the CHAC critical region and found 16 different mutations in individuals with chorea-acanthocytosis. CHAC encodes an evolutionarily conserved protein that is probably involved in protein sorting. 相似文献