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1.
The sex-linked fidget mutation abolishes Brn4/Pou3f4 gene expression in the embryonic inner ear 总被引:3,自引:0,他引:3
Phippard D Boyd Y Reed V Fisher G Masson WK Evans EP Saunders JC Crenshaw EB 《Human molecular genetics》2000,9(1):79-85
We have demonstrated that the phenotype of the mouse mutant sex-linked fidget ( slf ) is caused by developmental malformations of the inner ear that result in hearing loss and vestibular dysfunction. Recently, pilot mapping experiments suggested that the mouse Brn4 / Pou3f4 gene co-segregated with the slf locus on the mouse X chromosome. These mapping data, in conjunction with the observation that the vertical head-shaking phenotype of slf mutants is identical to that observed in mice with a targeted deletion of the Brn4 gene, suggested that slf is a mutant allele of the Brn4 gene. In this paper, we have identified the nature of the slf mutation, and demonstrated that it is an X chromosomal inversion with one breakpoint close to Brn4. This inversion selectively eliminates the expression of the Brn4 gene in the developing inner ear, but not the neural tube. Finally, these results demonstrate that the slf mutation is a good mouse model for the most prevalent form of X-linked congenital deafness in man, which is associated with mutations in the human Brn4 ortholog, POU3F4. 相似文献
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Skn-1a (Pou2f3) specifies taste receptor cell lineage 总被引:1,自引:0,他引:1
Functional diversification of taste cells is crucial for proper discrimination of taste qualities. We found the homeodomain protein Skn-1a (Pou2f3) to be expressed in sweet, umami and bitter taste cells. Skn-1a-deficient mice lacked electrophysiological and behavioral responses to sweet, umami and bitter tastes, as a result of a complete absence of sweet, umami and bitter cells and the concomitant expansion of sour cells. Skn-1a is critical for generating and balancing the diverse composition of taste cells. 相似文献
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Expressional profiling of prostate cancer risk SNPs at 11q13.5 identifies DGAT2 as a new target gene
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Riikka Nurminen Tommi Rantapero Swee C. Wong Daniel Fischer Rainer Lehtonen Teuvo L.J. Tammela Matti Nykter Tapio Visakorpi Tiina Wahlfors Johanna Schleutker 《Genes, chromosomes & cancer》2016,55(8):661-673
A total of nine non‐coding variants on 11q13.5 predispose men to prostate cancer (PrCa). rs200331695 within the EMSY intron is associated with aggressive PrCa and two high linkage disequilibrium (LD) groups of single‐nucleotide polymorphisms (SNPs) in the intergenic region are associated with PrCa death. Here, the cis‐effect of the SNPs on gene expression using expression quantitative trait loci analysis was investigated. The regulatory potential was screened in prostate tumors (n = 41) and in whole blood (n = 99). The results were validated in a second tumor set (n = 41), in lymphoblastoid cell lines (LCLs) (n = 38), and using the GTEx Portal. The effects of haplotypes were analyzed in the whole blood. The high LD SNPs (rs143975731, rs12277366, rs2155225, and rs2155222) were associated with DGAT2 expression in both tumors sets (screening P = 0.035–0.043; validation P = 0.005–0.018). The PrCa death‐associated alleles decreased the expression by two‐fold. rs200331695 decreased DGAT2 expression in LCLs (P = 0.006). The findings of SNPs regulating CAPN5 (P = 0.026–0.046) and AP001189.4 (P = 0.03–0.039) in the whole blood were not observed in LCLs, but the association with AP001189.4 expression was validated via the GTEx Portal (P = 8.7 × 10−5 to 4.3 × 10−4), which suggests that the high LD intergenic SNPs exert a tissue‐dependent effect on the expression of two genes. No haplotypes including the risk SNPs at 11q13.5 were associated with gene expression and PrCa. The findings indicate the functionality of the PrCa death‐predisposing SNPs rs143975731, rs12277366, rs2155225, and rs2155222 as DGAT2 regulators in prostate tumors. © 2016 Wiley Periodicals, Inc. 相似文献
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Whole genome gene copy number profiling of gastric cancer identifies PAK1 and KRAS gene amplification as therapy targets
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Ziliang Qian Guanshan Zhu Lili Tang Mei Wang Lianhai Zhang Jiangang Fu Chunlei Huang Shuqiong Fan Yun Sun Jing Lv Hua Dong Beirong Gao Xinying Su Dehua Yu Jie Zang Xiaolin Zhang Jiafu Ji Qunsheng Ji 《Genes, chromosomes & cancer》2014,53(11):883-894
Gastric cancer is the second leading cause of death from cancer worldwide, with an approximately 20% 5‐year survival rate. To identify molecular subtypes associated with the clinical prognosis, in addition to genetic aberrations for potential targeted therapeutics, we conducted a comprehensive whole‐genome analysis of 131 Chinese gastric cancer tissue specimens using whole‐genome array comparative genomic hybridization. The analyses revealed gene focal amplifications, including CTSB, PRKCI, PAK1, STARD13, KRAS, and ABCC4, in addition to ERBB2, FGFR2, and MET. The growth of PAK1‐amplified gastric cancer cells in vitro and in vivo was inhibited when the corresponding mRNA was knocked down. Furthermore, both KRAS amplification and KRAS mutation were identified in the gastric cancer specimens. KRAS amplification was associated with worse clinical outcomes, and the KRAS gene mutation predicted sensitivity to the MEK1/2 inhibitor AZD6244 in gastric cancer cell lines. In summary, amplified PAK1, as well as KRAS amplification/mutation, may represent unique opportunities for developing targeted therapeutics for the treatment of gastric cancer. © 2014 Wiley Periodicals, Inc. 相似文献
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Zenteno JC Buentello-Volante B Ayala-Ramirez R Villanueva-Mendoza C 《American journal of medical genetics. Part A》2011,155(5):1001-1006
The association of retinitis pigmentosa (RP) and microphthalmia has been reported in a number of familial and isolated cases. Here, the results of genetic analysis in a familial case of early RP associated with nanophthalmos are described. Two affected sibs were ascertained from an endogamous population in Mexico. A genome-wide linkage analysis was performed by means of an Affymetrix 250K microarray. Five large regions of homozygosity were demonstrated. The largest interval comprised 15.08 Mb at chromosome 1q31-32.1 and contained the Crumbs homologue-1, CRB1, a gene responsible for a number of recessive retinal dystrophies. Nucleotide sequence analysis demonstrated a c.1125C>G transversion in CRB1 exon 5, predicting a novel p.Tyr375X variant. To our knowledge this is the first instance in which a CRB1 mutation has been associated with early RP and nanophthalmos. Our results suggest a role for CRB1 in promoting axial growth of the eye. Clinical analysis of additional subjects with retinal dystrophies due to CRB1 mutations will help to identify if the high hyperopia, a frequently observed trait in these subjects, could be related to decreased eye axial length (nanophthalmos). 相似文献
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Lawrence P. Andrews Ariel E. Marciscano Charles G. Drake Dario A. A. Vignali 《Immunological reviews》2017,276(1):80-96
Despite the impressive impact of CTLA4 and PD1-PDL1-targeted cancer immunotherapy, a large proportion of patients with many tumor types fail to respond. Consequently, the focus has shifted to targeting alternative inhibitory receptors (IRs) and suppressive mechanisms within the tumor microenvironment. Lymphocyte activation gene-3 (LAG3) (CD223) is the third IR to be targeted in the clinic, consequently garnering considerable interest and scrutiny. LAG3 upregulation is required to control overt activation and prevent the onset of autoimmunity. However, persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression, contributing to a state of exhaustion manifest in impaired proliferation and cytokine production. The exact signaling mechanisms downstream of LAG3 and interplay with other IRs remain largely unknown. However, the striking synergy between LAG3 and PD1 observed in multiple settings, coupled with the contrasting intracellular cytoplasmic domain of LAG3 as compared with other IRs, highlights the potential uniqueness of LAG3. There are now four LAG3-targeted therapies in the clinic with many more in preclinical development, emphasizing the broad interest in this IR. Given the translational relevance of LAG3 and the heightened interest in the impact of dual LAG3/PD1 targeting in the clinic, the outcome of these trials could serve as a nexus; significantly increasing or dampening enthusiasm for subsequent targets in the cancer immunotherapeutic pipeline. 相似文献
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Evaluation of the Thyroid Transcription Factor-1 Gene (TITF1) as a Hirschsprung's Disease Locus 总被引:2,自引:0,他引:2
Maria-Mercè Garcia-Barceló Danny Ko-chun Lau Elly Sau-wai Ngan Thomas Yuk-yu Leon Ting-ting Liu Man-ting So Xiao-ping Miao Vincent Chi-hang Lui Kenneth Kak-yuen Wong Raymond William Ganster Daniel Thomas Cass Geoffrey David Hain Croaker Paul Kwong-hang Tam 《Annals of human genetics》2007,71(6):746-754
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Transcription profiling of platelet-derived growth factor-B-deficient mouse embryos identifies RGS5 as a novel marker for pericytes and vascular smooth muscle cells 总被引:10,自引:0,他引:10
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Bondjers C Kalén M Hellström M Scheidl SJ Abramsson A Renner O Lindahl P Cho H Kehrl J Betsholtz C 《The American journal of pathology》2003,162(3):721-729
All blood capillaries consist of endothelial tubes surrounded by mural cells referred to as pericytes. The origin, recruitment, and function of the pericytes is poorly understood, but the importance of these cells is underscored by the severe cardiovascular defects in mice genetically devoid of factors regulating pericyte recruitment to embryonic vessels, and by the association between pericyte loss and microangiopathy in diabetes mellitus. A general problem in the study of pericytes is the shortage of markers for these cells. To identify new markers for pericytes, we have taken advantage of the platelet-derived growth factor (PDGF)-B knockout mouse model, in which developing blood vessels in the central nervous system are almost completely devoid of pericytes. Using cDNA microarrays, we analyzed the gene expression in PDGF-B null embryos in comparison with corresponding wild-type embryos and searched for down-regulated genes. The most down-regulated gene present on our microarray was RGS5, a member of the RGS family of GTPase-activating proteins for G proteins. In situ hybridization identified RGS5 expression in brain pericytes, and in pericytes and vascular smooth muscle cells in certain other, but not all, locations. Absence of RGS5 expression in PDGF-B and PDGFR beta-null embryos correlated with pericyte loss in these mice. Residual RGS5 expression in rare pericytes suggested that RGS5 is a pericyte marker expressed independently of PDGF-B/R beta signaling. With RGS5 as a proof-of-principle, our data demonstrate the usefulness of microarray analysis of mouse models for abnormal pericyte development in the identification of new pericyte-specific markers. 相似文献
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《Biomaterials》2015
A drug delivery system to the inner ear using nanoparticles consisting of oligoarginine peptide (Arg8) conjugated to poly(amino acid) (poly(2-hydroxyethyl l-aspartamide; PHEA) was investigated to determine whether the limitations of low drug transport levels across the round window membrane (RWM) and poor transport into inner ear target cells, including hair cells and spiral ganglion, could be overcome. Three types of carrier materials, PHEA-g-C18, PHEA-g-Arg8, and PHEA-g-C18-Arg8, were synthesized to examine the effects of oligoarginine and morphology of the synthesized carriers. Nile red (NR) was used as a fluorescent indicator as well as to model a hydrophobic drug. Compared with PHEA-g-C18-NR nanoparticles, the oligoarginine-conjugated nanoparticles of PHEA-g-C18-Arg8-NR and PHEA-g-Arg8-NR entered into HEI-OC1 cells at significant levels. Furthermore, the strongest fluorescence intensity was observed in nuclei when PHEA-g-C18-Arg8 nanoparticles were used. The high uptake rates of PHEA-g-C18 and PHEA-g-C18-Arg8 nanoparticles were observed in ex vivo experiments using hair cells. After the delivery of PHEA-g-C18-Arg8 nanoparticles with reporter gene transfer, EGFP (enhanced green fluorescent protein) expression was monitored as an indicator of gene delivery. In the inner ear cells, PHEA-g-C18-Arg8 nanoparticles showed comparable or better transfection capabilities than the commercially available Lipofectamine reagent. PHEA-g-C18-Arg8 penetrated in vivo across the RWM of C57/BL6 mice with Nile red staining and GFP expression in various inner ear tissues. In conclusion, PHEA-g-C18-Arg8 nanoparticles were successfully transported into the inner ear through the intratympanic route and are proposed as promising candidates as delivery carriers to address inner ear diseases. 相似文献
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Targeted gene deletion in Leishmania major identifies leishmanolysin (GP63) as a virulence factor 总被引:5,自引:0,他引:5
Joshi PB Kelly BL Kamhawi S Sacks DL McMaster WR 《Molecular and biochemical parasitology》2002,120(1):33-40
Leishmanolysin, the Leishmania surface metalloproteinase of 63 kDa (GP63) has been described as a parasite virulence factor and is involved in the direct interaction of promastigotes and host macrophage receptors and interaction with the complement cascade. To study the role of leishmanolysin in the pathogenesis and virulence of Leishmania major, targeted gene replacement was used to delete the entire 20 kb region containing all seven leishmanolysin genes (gp63 genes 1-7). The resulting L. major leishmanolysin deficient mutants showed normal development inside the sand fly vector, however, promastigotes recovered from sand flies or from culture showed an increase in sensitivity to complement-mediated lysis and a delay in lesion formation in BALB/c animals. The phenotypic differences could be significantly improved by expression of a cloned leishmanolysin gene. These results demonstrate that leishmanolysin is a vital virulence factor in Leishmania pathogenesis. 相似文献
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Kok Yvette J.M.de; Merkx Gerard F.M.; van der Maarel Silvere M.; Huber Irene; Malcolm Susan; Ropers Hans-Hilger; Cremers Frans P.M. 《Human molecular genetics》1995,4(11):2145-2150
X-linked deafness with stapes fixation (DFN3) is caused by mutationsin the POU3F4 gene at Xq21.1. By employing pulsed field gelelectrophoresis (PFGE) we identified a chromosomal aberrationin the DNA of a DFN3 patient who did not show alterations inthe open reading frame (ORF) of POU3F4. Southern blot analysisindicated that a DNA segment of 150 kb, located 170 kb proximalto the POU3F4 gene, was duplicated. Fluorescence in situ hybridization(FISH) analysis, PFGE, and detailed Southern analysis revealedthat this duplication is part of a more complex rearrangementincluding a paracentric inversion involving the Xq21.1 region,and presumably the Xq21.3 region. Since at least two DFN3-associatedminideletions are situated proximal to the duplicated segment,the inversion most likely disconnects the POU3F4 gene from aregulatory element which is located at a distance of at least400 kb upstream of the POU3F4 gene. 相似文献
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Identification of a hot spot for microdeletions in patients with X- linked deafness type 3 (DFN3) 900 kb proximal to the DFN3 gene POU3F4 总被引:5,自引:1,他引:5
de Kok YJ; Vossenaar ER; Cremers CW; Dahl N; Laporte J; Hu LJ; Lacombe D; Fischel-Ghodsian N; Friedman RA; Parnes LS; Thorpe P; Bitner-Glindzicz M; Pander HJ; Heilbronner H; Graveline J; den Dunnen JT; Brunner HG; Ropers HH; Cremers FP 《Human molecular genetics》1996,5(9):1229-1235
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Transcription from the gene encoding the herpesvirus entry receptor nectin-1 (HveC) in nervous tissue of adult mouse 总被引:13,自引:0,他引:13
Hepatitis C virus core protein, in addition to being a component of the viral capsid, has a number of regulatory functions. Here we showed two bodies of evidence indicating that a fraction of the core protein species is a substrate of the ubiquitin (Ub)-proteasome pathway of targeted proteolysis. First, the core protein processing the C-terminal hydrophobic region is metabolically unstable, and incubation with a proteasome inhibitor led to a significant accumulation of the protein. Second, an in vivo ubiquitylation assay indicates conjugation of multi-Ub chain to the unstable core protein. In contrast, a stable form of core protein, p21, is also able to be ubiquitylated, but it links to a single or only a few Ub moiety. Therefore, processing event(s) at the C-terminal hydrophobic domain of HCV core protein may affect the ubiquitylation pathway, particularly the efficiency of the multi-Ub chain assembly, resulting in stable, matured core proteins. 相似文献