排序方式: 共有58条查询结果,搜索用时 15 毫秒
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Lee JE Silhavy JL Zaki MS Schroth J Bielas SL Marsh SE Olvera J Brancati F Iannicelli M Ikegami K Schlossman AM Merriman B Attié-Bitach T Logan CV Glass IA Cluckey A Louie CM Lee JH Raynes HR Rapin I Castroviejo IP Setou M Barbot C Boltshauser E Nelson SF Hildebrandt F Johnson CA Doherty DA Valente EM Gleeson JG 《Nature genetics》2012,44(2):193-199
Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function. However, its relationship to disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (JBTS), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein. We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme. Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction. 相似文献
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A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures 总被引:1,自引:0,他引:1
Sharp AJ Mefford HC Li K Baker C Skinner C Stevenson RE Schroer RJ Novara F De Gregori M Ciccone R Broomer A Casuga I Wang Y Xiao C Barbacioru C Gimelli G Bernardina BD Torniero C Giorda R Regan R Murday V Mansour S Fichera M Castiglia L Failla P Ventura M Jiang Z Cooper GM Knight SJ Romano C Zuffardi O Chen C Schwartz CE Eichler EE 《Nature genetics》2008,40(3):322-328
We report a recurrent microdeletion syndrome causing mental retardation, epilepsy and variable facial and digital dysmorphisms. We describe nine affected individuals, including six probands: two with de novo deletions, two who inherited the deletion from an affected parent and two with unknown inheritance. The proximal breakpoint of the largest deletion is contiguous with breakpoint 3 (BP3) of the Prader-Willi and Angelman syndrome region, extending 3.95 Mb distally to BP5. A smaller 1.5-Mb deletion has a proximal breakpoint within the larger deletion (BP4) and shares the same distal BP5. This recurrent 1.5-Mb deletion contains six genes, including a candidate gene for epilepsy (CHRNA7) that is probably responsible for the observed seizure phenotype. The BP4-BP5 region undergoes frequent inversion, suggesting a possible link between this inversion polymorphism and recurrent deletion. The frequency of these microdeletions in mental retardation cases is approximately 0.3% (6/2,082 tested), a prevalence comparable to that of Williams, Angelman and Prader-Willi syndromes. 相似文献
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Cox JJ Reimann F Nicholas AK Thornton G Roberts E Springell K Karbani G Jafri H Mannan J Raashid Y Al-Gazali L Hamamy H Valente EM Gorman S Williams R McHale DP Wood JN Gribble FM Woods CG 《Nature》2006,444(7121):894-898
The complete inability to sense pain in an otherwise healthy individual is a very rare phenotype. In three consanguineous families from northern Pakistan, we mapped the condition as an autosomal-recessive trait to chromosome 2q24.3. This region contains the gene SCN9A, encoding the alpha-subunit of the voltage-gated sodium channel, Na(v)1.7, which is strongly expressed in nociceptive neurons. Sequence analysis of SCN9A in affected individuals revealed three distinct homozygous nonsense mutations (S459X, I767X and W897X). We show that these mutations cause loss of function of Na(v)1.7 by co-expression of wild-type or mutant human Na(v)1.7 with sodium channel beta(1) and beta(2) subunits in HEK293 cells. In cells expressing mutant Na(v)1.7, the currents were no greater than background. Our data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans. These findings should stimulate the search for novel analgesics that selectively target this sodium channel subunit. 相似文献
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Silvia Lisa Massimiliano Meli Gema Cabello Ruth Gabizon Giorgio Colombo María Gasset 《Cellular and molecular life sciences : CMLS》2010,67(16):2825-2838
The conversion of the cellular prion protein (PrPC) into its disease-associated form (PrPSc) involves a major conformational change and the accumulation of sulfoxidized methionines. Computational and synthetic approaches
have shown that this change in the polarity of M206 and M213 impacts the C-terminal domain native α-fold allowing the flexibility
required for the structural conversion. To test the effect in the full-length molecule with site-specificity, we have generated
M-to-S mutations. Molecular dynamics simulations show that the replacement indeed perturbs the native state. When this mutation
is placed at the conserved methionines of HaPrP(23–231), only substitutions at the Helix-3 impair the α-fold, stabilizing
a non-native state with perturbed secondary structure, loss of native tertiary contacts, increased surface hydrophobicity,
reduced thermal stability and an enhanced tendency to aggregate into protofibrillar polymers. Our work supports that M206
and M213 function as α-fold gatekeepers and suggests that their redox state regulate misfolding routes. 相似文献
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A rapidly growing literature emphasizes the importance of evaluating the forecast accuracy of empirical models on the basis of density (as opposed to point) forecasting performance. We propose a test statistic for the null hypothesis that two competing models have equal density forecast accuracy. Monte Carlo simulations suggest that the test, which has a known limiting distribution, displays satisfactory size and power properties. The use of the test is illustrated with an application to exchange rate forecasting. Copyright © 2004 John Wiley & Sons, Ltd. 相似文献
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