排序方式: 共有68条查询结果,搜索用时 15 毫秒
41.
Josephina?A.N. Meester Laura Southgate Anna-Barbara Stittrich Hanka Venselaar Sander?J.A. Beekmans Nicolette den?Hollander Emilia?K. Bijlsma Appolonia Helderman-van?den?Enden Joke?B.G.M. Verheij Gustavo Glusman Jared?C. Roach Anna Lehman Millan?S. Patel Bert?B.A. de?Vries Claudia Ruivenkamp Peter Itin Katrina Prescott Sheila Clarke Richard Trembath Martin Zenker Maja Sukalo Lut Van?Laer Bart Loeys Wim Wuyts 《American journal of human genetics》2015,97(3):475-482
Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the presence of aplasia cutis congenita (ACC) of the scalp vertex and terminal limb-reduction defects. Cardiovascular anomalies are also frequently observed. Mutations in five genes have been identified as a cause for AOS prior to this report. Mutations in EOGT and DOCK6 cause autosomal-recessive AOS, whereas mutations in ARHGAP31, RBPJ, and NOTCH1 lead to autosomal-dominant AOS. Because RBPJ, NOTCH1, and EOGT are involved in NOTCH signaling, we hypothesized that mutations in other genes involved in this pathway might also be implicated in AOS pathogenesis. Using a candidate-gene-based approach, we prioritized DLL4, a critical NOTCH ligand, due to its essential role in vascular development in the context of cardiovascular features in AOS-affected individuals. Targeted resequencing of the DLL4 gene with a custom enrichment panel in 89 independent families resulted in the identification of seven mutations. A defect in DLL4 was also detected in two families via whole-exome or genome sequencing. In total, nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants, the latter encompassing four mutations that replace or create cysteine residues, which are most likely critical for maintaining structural integrity of the protein. Affected individuals with DLL4 mutations present with variable clinical expression with no emerging genotype-phenotype correlations. Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder. 相似文献
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Alexandru A. Hennrich Bevan Sawatsky Rosalía Santos-Mandujano Dominic H. Banda Martina Oberhuber Anika Schopf Verena Pfaffinger Kevin Wittwer Christiane Riedel Christian K. Pfaller Karl-Klaus Conzelmann 《PLoS pathogens》2021,17(4)
Vaccines of outstanding efficiency, safety, and public acceptance are needed to halt the current SARS-CoV-2 pandemic. Concerns include potential side effects caused by the antigen itself and safety of viral DNA and RNA delivery vectors. The large SARS-CoV-2 spike (S) protein is the main target of current COVID-19 vaccine candidates but can induce non-neutralizing antibodies, which might cause vaccination-induced complications or enhancement of COVID-19 disease. Besides, encoding of a functional S in replication-competent virus vector vaccines may result in the emergence of viruses with altered or expanded tropism. Here, we have developed a safe single round rhabdovirus replicon vaccine platform for enhanced presentation of the S receptor-binding domain (RBD). Structure-guided design was employed to build a chimeric minispike comprising the globular RBD linked to a transmembrane stem-anchor sequence derived from rabies virus (RABV) glycoprotein (G). Vesicular stomatitis virus (VSV) and RABV replicons encoding the minispike not only allowed expression of the antigen at the cell surface but also incorporation into the envelope of secreted non-infectious particles, thus combining classic vector-driven antigen expression and particulate virus-like particle (VLP) presentation. A single dose of a prototype replicon vaccine complemented with VSV G, VSVΔG-minispike-eGFP (G), stimulated high titers of SARS-CoV-2 neutralizing antibodies in mice, equivalent to those found in COVID-19 patients, and protected transgenic K18-hACE2 mice from COVID-19-like disease. Homologous boost immunization further enhanced virus neutralizing activity. The results demonstrate that non-spreading rhabdovirus RNA replicons expressing minispike proteins represent effective and safe alternatives to vaccination approaches using replication-competent viruses and/or the entire S antigen. 相似文献
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Daniel D. Tune Frank Hennrich Simone Dehm Michael F. G. Klein Konstantin Glaser Alexander Colsmann Joseph G. Shapter Uli Lemmer Manfred M. Kappes Ralph Krupke Benjamin S. Flavel 《Liver Transplantation》2013,3(8):1091-1097
The mechanism of action of nanotube‐silicon heterojunction solar cells is under discussion with literature reports suggesting either p‐n or Schottky junction characteristics. The crux of the issue is whether the nanotubes contribute to the observed photocurrent or not. In order to further understand the mechanism of action of these solar cells, devices were fabricated using nanotubes sorted by (n,m) species, so that the excitonic transition is well defined and is outside the range of absorption of silicon and such that any contribution to the photocurrent from the nanotubes should be easily resolved from that of the silicon by analysis of the photocurrent spectrum. The devices exhibited the photocurrent spectra of silicon only, indicating that the nanotubes do not contribute to the photocurrent. However, by changing the back contact electrode material, results were obtained that appear to show such a contribution. 相似文献
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Bryde S Hennrich H Verhulst PM Devaux PF Lenoir G Holthuis JC 《The Journal of biological chemistry》2010,285(52):40562-40572
Members of the P(4) subfamily of P-type ATPases catalyze phospholipid transport and create membrane lipid asymmetry in late secretory and endocytic compartments. P-type ATPases usually pump small cations and the transport mechanism involved appears conserved throughout the family. How this mechanism is adapted to flip phospholipids remains to be established. P(4)-ATPases form heteromeric complexes with CDC50 proteins. Dissociation of the yeast P(4)-ATPase Drs2p from its binding partner Cdc50p disrupts catalytic activity (Lenoir, G., Williamson, P., Puts, C. F., and Holthuis, J. C. (2009) J. Biol. Chem. 284, 17956-17967), suggesting that CDC50 subunits play an intimate role in the mechanism of transport by P(4)-ATPases. The human genome encodes 14 P(4)-ATPases while only three human CDC50 homologues have been identified. This implies that each human CDC50 protein interacts with multiple P(4)-ATPases or, alternatively, that some human P(4)-ATPases function without a CDC50 binding partner. Here we show that human CDC50 proteins each bind multiple class-1 P(4)-ATPases, and that in all cases examined, association with a CDC50 subunit is required for P(4)-ATPase export from the ER. Moreover, we find that phosphorylation of the catalytically important Asp residue in human P(4)-ATPases ATP8B1 and ATP8B2 is critically dependent on their CDC50 subunit. These results indicate that CDC50 proteins are integral part of the P(4)-ATPase flippase machinery. 相似文献
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Vissers LE Lausch E Unger S Campos-Xavier AB Gilissen C Rossi A Del Rosario M Venselaar H Knoll U Nampoothiri S Nair M Spranger J Brunner HG Bonafé L Veltman JA Zabel B Superti-Furga A 《American journal of human genetics》2011,(5):2609-615
We used whole-exome sequencing to study three individuals with a distinct condition characterized by short stature, chondrodysplasia with brachydactyly, congenital joint dislocations, cleft palate, and facial dysmorphism. Affected individuals carried homozygous missense mutations in IMPAD1, the gene coding for gPAPP, a Golgi-resident nucleotide phosphatase that hydrolyzes phosphoadenosine phosphate (PAP), the byproduct of sulfotransferase reactions, to AMP. The mutations affected residues in or adjacent to the phosphatase active site and are predicted to impair enzyme activity. A fourth unrelated patient was subsequently found to be homozygous for a premature termination codon in IMPAD1. Impad1 inactivation in mice has previously been shown to produce chondrodysplasia with abnormal joint formation and impaired proteoglycan sulfation. The human chondrodysplasia associated with gPAPP deficiency joins a growing number of skeletoarticular conditions associated with defective synthesis of sulfated proteoglycans, highlighting the importance of proteoglycans in the development of skeletal elements and joints. 相似文献
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Tae-Jun Kwon Se-Kyung Oh Hong-Joon Park Osamu Sato Hanka Venselaar Soo Young Choi SungHee Kim Kyu-Yup Lee Jinwoong Bok Sang-Heun Lee Gert Vriend Mitsuo Ikebe Un-Kyung Kim Jae Young Choi 《Open biology》2014,4(7)
Mutations in five unconventional myosin genes have been associated with genetic hearing loss (HL). These genes encode the motor proteins myosin IA, IIIA, VI, VIIA and XVA. To date, most mutations in myosin genes have been found in the Caucasian population. In addition, only a few functional studies have been performed on the previously reported myosin mutations. We performed screening and functional studies for mutations in the MYO1A and MYO6 genes in Korean cases of autosomal dominant non-syndromic HL. We identified four novel heterozygous mutations in MYO6. Three mutations (p.R825X, p.R991X and Q918fsX941) produce a premature truncation of the myosin VI protein. Another mutation, p.R205Q, was associated with diminished actin-activated ATPase activity and actin gliding velocity of myosin VI in an in vitro analysis. This finding is consistent with the results of protein modelling studies and corroborates the pathogenicity of this mutation in the MYO6 gene. One missense variant, p.R544W, was found in the MYO1A gene, and in silico analysis suggested that this variant has deleterious effects on protein function. This finding is consistent with the results of protein modelling studies and corroborates the pathogenic effect of this mutation in the MYO6 gene. 相似文献
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Zafar Iqbal Marjolein?H. Willemsen Marie-Amélie Papon Luciana Musante Marco Benevento Hao Hu Hanka Venselaar Willemijn?M. Wissink-Lindhout Anneke?T. Vulto-van?Silfhout Lisenka?E.L.M. Vissers Arjan?P.M. de?Brouwer Sylviane Marouillat Thomas?F. Wienker Hans?Hilger Ropers Kimia Kahrizi Nael Nadif?Kasri Hossein Najmabadi Frédéric Laumonnier Tjitske Kleefstra Hans van?Bokhoven 《American journal of human genetics》2015,96(3):386-396
We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses. 相似文献
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A growing culture of Streptomyces lydicus converted biotin-14C to α-dehydrobiotin-14C. The conversion was demonstrated by isolating crystalline α-dehydrobiotin-14C from fermentation liquors supplemented with biotin-14C. The addition of pimelic acid-14C to the growing culture did not produce any radioactive α-dehydrobiotin. α-Dehydrobiotin did not substitute for biotin in Lactobacillus plantarum or in Saccharomyces cerevisiae. Antimicrobial activity of α-dehydrobiotin was abolished by avidin. α-Dehydrobiotin appears to be different from several biotin vitamers described in the literature. It is concluded that α-dehydrobiotin is a product of biotin catabolism in S. lydicus. 相似文献