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61.
62.
Evidence for linkage of the central core disease locus to the proximal long arm of human chromosome 19 总被引:5,自引:0,他引:5
Central core disease of muscle (CCD; MIM 117000) is a rare inheritable myopathy that is frequently found in association with susceptibility to malignant hyperthermia (MHS). This observation has prompted us to perform a linkage study in CCD families using various chromosome 19q probes that are linked to the MHS locus and map close to the ryanodine receptor gene (RYR1), a strong MHS candidate gene. Our genetic linkage data support a location of the CCD gene on proximal 19q13.1 and thus suggest that CCD and MHS may be allelic. 相似文献
63.
Lu C Stewart DJ Lee JJ Ji L Ramesh R Jayachandran G Nunez MI Wistuba II Erasmus JJ Hicks ME Grimm EA Reuben JM Baladandayuthapani V Templeton NS McMannis JD Roth JA 《PloS one》2012,7(4):e34833
Background
Tumor suppressor gene TUSC2/FUS1 (TUSC2) is frequently inactivated early in lung cancer development. TUSC2 mediates apoptosis in cancer cells but not normal cells by upregulation of the intrinsic apoptotic pathway. No drug strategies currently exist targeting loss-of–function genetic abnormalities. We report the first in-human systemic gene therapy clinical trial of tumor suppressor gene TUSC2.Methods
Patients with recurrent and/or metastatic lung cancer previously treated with platinum-based chemotherapy were treated with escalating doses of intravenous N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP):cholesterol nanoparticles encapsulating a TUSC2 expression plasmid (DOTAP:chol-TUSC2) every 3 weeks.Results
Thirty-one patients were treated at 6 dose levels (range 0.01 to 0.09 milligrams per kilogram). The MTD was determined to be 0.06 mg/kg. Five patients achieved stable disease (2.6–10.8 months, including 2 minor responses). One patient had a metabolic response on positron emission tomography (PET) imaging. RT-PCR analysis detected TUSC2 plasmid expression in 7 of 8 post-treatment tumor specimens but not in pretreatment specimens and peripheral blood lymphocyte controls. Proximity ligation assay, performed on paired biopsies from 3 patients, demonstrated low background TUSC2 protein staining in pretreatment tissues compared with intense (10–25 fold increase) TUSC2 protein staining in post-treatment tissues. RT-PCR gene expression profiling analysis of apoptotic pathway genes in two patients with high post-treatment levels of TUSC2 mRNA and protein showed significant post-treatment changes in the intrinsic apoptotic pathway. Twenty-nine genes of the 82 tested in the apoptosis array were identified by Igenuity Pathway Analysis to be significantly altered post-treatment in both patients (Pearson correlation coefficient 0.519; p<0.01).Conclusions
DOTAP:chol-TUSC2 can be safely administered intravenously in lung cancer patients and results in uptake of the gene by human primary and metastatic tumors, transgene and gene product expression, specific alterations in TUSC2-regulated pathways, and anti-tumor effects (to our knowledge for the first time for systemic DOTAP:cholesterol nanoparticle gene therapy).Trial Registration
ClinicalTrials.gov NCT00059605相似文献64.
Hot spot of recombination within DXS164 in the Duchenne muscular dystrophy gene. 总被引:2,自引:3,他引:2 下载免费PDF全文
T Grimm B Müller M Dreier E Kind T Bettecken G Meng C R Müller 《American journal of human genetics》1989,45(3):368-372
The DMD gene, which spans more than 2,000 kbp, has been assigned to band Xp21 of the X chromosome. Two subclones (PERT 87-1 and PERT 87-15) of the intragenic locus DXS164 physically are separated by approximately 60 kbp. Linkage studies were done in 49 informative DMD families by using the LINKAGE program. Crossing-over between the loci studied occurred in four families. A recombination rate of 4% (support interval [Zmax-1] 1%-10%), which was 54 (support interval 14-135-fold) times higher than expected, was found with a maximum lod score of 13.50. These data suggest a hot spot for recombination within DXS164. 相似文献
65.
Structural and functional analyses of methyl-lysine binding by the malignant brain tumour repeat protein Sex comb on midleg 总被引:2,自引:0,他引:2 下载免费PDF全文
Grimm C de Ayala Alonso AG Rybin V Steuerwald U Ly-Hartig N Fischle W Müller J Müller CW 《EMBO reports》2007,8(11):1031-1037
Sex comb on midleg (Scm) is a member of the Polycomb group of proteins involved in the maintenance of repression of Hox and other developmental control genes in Drosophila. The two malignant brain tumour (MBT) repeats of Scm form a domain that preferentially binds to monomethylated lysine residues either as a free amino acid or in the context of peptides, while unmodified or di- or trimethylated lysine residues are bound with significantly lower affinity. The crystal structure of a monomethyl-lysine-containing histone tail peptide bound to the MBT repeat domain shows that the methyl-lysine side chain occupies a binding pocket in the second MBT repeat formed by three conserved aromatic residues and one aspartate. Insertion of the monomethylated side chain into this pocket seems to be the main contributor to the binding affinity. Functional analyses in Drosophila show that the MBT domain of Scm and its methyl-lysine-binding activity are required for repression of Hox genes. 相似文献
66.
Viktor Demko Andrej Pavlovič Danka Valková L’udmila Slováková Bernhard Grimm Ján Hudák 《Planta》2009,230(1):165-176
Light-independent chlorophyll (Chl) biosynthesis is a prerequisite for the assembly of photosynthetic pigment–protein complexes
in the dark. Dark-grown Larix decidua Mill. seedlings synthesize Chl only in the early developmental stages and their Chl level rapidly declines during the subsequent
development. Our analysis of the key regulatory steps in Chl biosynthesis revealed that etiolation of initially green dark-grown
larch cotyledons is connected with decreasing content of glutamyl-tRNA reductase and reduced 5-aminolevulinic acid synthesizing
capacity. The level of the Chl precursor protochlorophyllide also declined in the developing larch cotyledons. Although the
genes chlL, chlN and chlB encoding subunits of the light-independent protochlorophyllide oxidoreductase were constitutively expressed in the larch
seedlings, the accumulation of the ChlB subunit was developmentally regulated and ChlB content decreased in the fully developed
cotyledons. The efficiency of chlB RNA-editing was also reduced in the mature dark-grown larch seedlings. In contrast to larch, dark-grown seedlings of Picea abies (L.) Karst. accumulate Chl throughout their whole development and show a different control of ChlB expression. Analysis of
the plastid ultrastructure, photosynthetic proteins by Western blotting and photosynthetic parameters by gas exchange and
Chl fluorescence measurements provide additional experimental proofs for differences between dark and light Chl biosynthesis
in spruce and larch seedlings. 相似文献
67.
M Wehnert G Machill T Grimm M Janka R Camman W Schr?der F H Herrmann 《Human heredity》1991,41(6):364-369
In a large German family with Emery-Dreifuss muscular dystrophy (EDMD) linkage analysis was performed using the factor IX gene (F9), the factor VIII:C gene (F8), the anonymous DNA probe DXS52, and DXS15 as markers. Tight linkage was found between the EDMD locus and the F8 probe (Zmax = 1.19; theta max = 0.00), DXS15 (Zmax = 1.75; theta max = 0.00) and DXS52 (Zmax = 2.26; theta max = 0.00). Weak linkage was found to F9 (Zmax = 0.02; theta max = 0.43). The data from the literature and our results suggest that the gene locus of EDMD is close to F8 (confidence interval theta = 0-0.07). The new linkage data are useful for carrier detection and diagnosis of EDMD patients before onset of major clinical signs. 相似文献
68.
With the increasing possibilities of genetic testing in clinical practice, genetic counseling becomes more and more important. Such counseling involves an attempt to answer questions and solve problems in connection with a possible genetic disorder. Reasons for genetic counseling are, among others, a possible genetic disorder in a child, a parent or a relative, advanced parental age, consanguinity, multiple pregnancy loss, stillbirths, infertility, and possible mutagenic or teratogenic exposure. Prenatal diagnosis, predictive and heterozygosity testing may have implications which differ from those of conventional diagnoses in medicine. The decision for testing should be made informed after genetic counseling. An overview of the aims, practical aspects and possible reasons for genetic counseling is provided. 相似文献
69.