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1.
Lasry I Seo YA Ityel H Shalva N Pode-Shakked B Glaser F Berman B Berezovsky I Goncearenco A Klar A Levy J Anikster Y Kelleher SL Assaraf YG 《The Journal of biological chemistry》2012,287(35):29348-29361
Zinc is an essential mineral, and infants are particularly vulnerable to zinc deficiency as they require large amounts of zinc for their normal growth and development. We have recently described the first loss-of-function mutation (H54R) in the zinc transporter ZnT-2 (SLC30A2) in mothers with infants harboring transient neonatal zinc deficiency (TNZD). Here we identified and characterized a novel heterozygous G87R ZnT-2 mutation in two unrelated Ashkenazi Jewish mothers with infants displaying TNZD. Transient transfection of G87R ZnT-2 resulted in endoplasmic reticulum-Golgi retention, whereas the WT transporter properly localized to intracellular secretory vesicles in HC11 and MCF-7 cells. Consequently, G87R ZnT-2 showed decreased stability compared with WT ZnT-2 as revealed by Western blot analysis. Three-dimensional homology modeling based on the crystal structure of YiiP, a close zinc transporter homologue from Escherichia coli, revealed that the basic arginine residue of the mutant G87R points toward the membrane lipid core, suggesting misfolding and possible loss-of-function. Indeed, functional assays including vesicular zinc accumulation, zinc secretion, and cytoplasmic zinc pool assessment revealed markedly impaired zinc transport in G87R ZnT-2 transfectants. Moreover, co-transfection experiments with both mutant and WT transporters revealed a dominant negative effect of G87R ZnT-2 over the WT ZnT-2; this was associated with mislocalization, decreased stability, and loss of zinc transport activity of the WT ZnT-2 due to homodimerization observed upon immunoprecipitation experiments. These findings establish that inactivating ZnT-2 mutations are an underlying basis of TNZD and provide the first evidence for the dominant inheritance of heterozygous ZnT-2 mutations via negative dominance due to homodimer formation. 相似文献
2.
The Molecular Basis of Canavan (Aspartoacylase Deficiency) Disease in European Non-Jewish Patients 总被引:3,自引:1,他引:2 下载免费PDF全文
A. Shaag Y. Anikster E. Christensen J. Z. Glustein A. Fois H. Michelakakis F. Nigro E. Pronicka A. Ribes M. T. Zabot O. N. Elpeleg 《American journal of human genetics》1995,57(3):572-580
Canavan disease is an infantile neurodegenerative disease that is due to aspartoacylase deficiency. The disease has been reported mainly in Ashkenazi Jews but also occurs in other ethnic groups. Determination of enzymatic activity for carrier detection and prenatal diagnosis is considered unreliable. In the present study, nine mutations were found in the aspartoacylase gene of 19 non-Jewish patients. These included four point mutations (A305E [39.5% of the mutated alleles], C218X [15.8%], F295S [2.6%], and G274R [5.3%]); four deletion mutations (827delGT [5.3%], 870del4 [2.6%], 566del7 [2.6%], and 527del6 [2.6%]); and one exon skip (527del108 [5.3%]). The A305E mutation is pan-European and probably the most ancient mutation, identified in patients of Greek, Polish, Danish, French, Spanish, Italian, and British origin. In contrast, the G274R and 527del108 mutations were found only in patients of Turkish origin, and the C218X mutation was identified only in patients of Gypsy origin. Homozygosity for the A305E mutation was identified in patients with both the severe and the mild forms of Canavan disease. Mutations were identified in 31 of the 38 alleles, resulting in an overall detection rate of 81.6%. All nine mutations identified in non-Jewish patients reside in exons 4–6 of the aspartoacylase gene. The results would enable accurate genetic counseling in the families of 13 (68.4%) of 19 patients, in whom two mutations were identified in the aspartoacylase cDNA. 相似文献
3.
Zilkah Shmuel Faingersh Evgenia Rotbaum Arie Dvorkin Rima Eilam Tamar Anikster Yehoshua 《Plant Cell, Tissue and Organ Culture》1999,59(3):209-215
Alternate host plants of cereal rust fungi are necessary for studying the rust sexual cycle and pathogenicity. These plants
are usually difficult to propagate through cloning, while seed-propagated plants may have variable responses to the pathogen.
To overcome these obstacles, tissue culture, under controlled and aseptic conditions, was utilized for clonal propagation
and in vitro inoculation of the following species: Rhamnus palaestinus Boiss., the alternate host of oat (Avena spp.) crown rust (Puccinia coronata Corda); Thalictrum speciosissimum L., the alternate host of brown leaf rust of wheat (Puccinia recondita f. sp. tritici Eriks. & Henn.); and Lycopsis arvensis L., the alternate host of rye (Secala spp.) leaf rust (Puccinia recondita f. sp. recondita Rob. & Desm.). Shoot culture procedures for initial establishment and proliferation were developed for all three alternate
host species. Shoot cultures were multiplied at rates ranging from 0.3 to 1.7 shoots/week. Successful infection following
inoculation with teliospores of the corresponding rust fungi was obtained for R. palaestinus and T. speciosissimum but not for L. arvensis. The hardening and acclimatization efficiency of rooted T. speciosissimum and L. arvensis was of 80–90%. The propagation efficiency for R. palaestinus was not successful because of the low rate and poor quality of its rooting. It is concluded that the in vitro system might be used as an alternative method for inoculation and multiplication of alternate hosts of cereal rusts, although
more experimentation is needed to define accurately the appropriate conditions for the proper infection response.
This revised version was published online in June 2006 with corrections to the Cover Date. 相似文献
4.
One of the intriguing issues concerning the dynamics of plant genomes is the occurrence of intraspecific variation in nuclear DNA amount. The aim of this work was to assess the ranges of intraspecific, interspecific, and intergeneric variation in nuclear DNA content of diploid species of the tribe Triticeae (Poaceae) and to examine the relation between life form or habitat and genome size. Altogether, 438 plants representing 272 lines that belong to 22 species were analyzed. Nuclear DNA content was estimated by flow cytometry. Very small intraspecific variation in DNA amount was found between lines of Triticeae diploid species collected from different habitats or between different morphs. In contrast to the constancy in nuclear DNA amount at the intraspecific level, there are significant differences in genome size between the various diploid species. Within the genus Aegilops, the 1C DNA amount ranged from 4.84 pg in A. caudata to 7.52 pg in A. sharonensis; among genera, the 1C DNA amount ranged from 4.18 pg in Heteranthelium piliferum to 9.45 pg in Secale montanum. No evidence was found for a smaller genome size in annual, self-pollinating species relative to perennial, cross-pollinating ones. Diploids that grow in the southern part of the group's distribution have larger genomes than those growing in other parts of the distribution. The contrast between the low variation at the intraspecific level and the high variation at the interspecific one suggests that changes in genome size originated in close temporal proximity to the speciation event, i.e., before, during, or immediately after it. The possible effects of sudden changes in genome size on speciation processes are discussed. 相似文献
5.
We tested the importance of microenvironmental topographic parameters as predictors of emmer wheat genetic variation using three classes of single-locus (or at most several-loci) genetic markers (allozymes, glutenins, and qualitative traits) and two classes of markers of polygenic inheritance (phenological and morphological traits). Canonical correspondence analysis (CCA) and redundancy analysis (RDA) detected a significant effect of spatially structured environmental variation on genetic differences between plants for allozymes, glutenins, and quantitative morphological and phenological traits. However, after removing a spatial component of variation in partial CCA and partial RDA, the relationship of the remaining environmental variation with these genetic markers could be explained by chance alone, allowing us to rule out microniche topographic specialization in emmer wheat. Topographic autocorrelation exhibited a certain degree of similarity with genetic marker autocorrelation, indicating similar scales of environmental heterogeneity and seed flow. The detected population genetic structure agrees with one expected under isolation by distance as a result of limited gene flow. A negative relationship of genetic similarity with the logarithm of distance between plants was detected for both molecular markers and quantitative traits, which differed in the strength but not the pattern of association. 相似文献
6.
The frequency of the C854 mutation in the aspartoacylase gene in Ashkenazi Jews in Israel. 总被引:5,自引:3,他引:2 下载免费PDF全文
O. N. Elpeleg Y. Anikster V. Barash D. Branski A. Shaag 《American journal of human genetics》1994,55(2):287-288
Canavan disease (CD) is an infantile neurodegenerative disease that is transmitted in an autosomal recessive manner and has mainly been reported in Ashkenazi Jewish families. The primary enzymatic defect is aspartoacylase deficiency, and an A-to-C transition at nucleotide 854 of the cDNA has recently been reported. We screened 18 patients with CD and 879 healthy individuals, all Israeli Ashkenazi Jews, for the mutation. All 18 patients were homozygotes for the mutation, and 15 heterozygotes were found among the healthy individuals. The results disclose a carrier rate of 1:59 and suggest that a screening for the mutation is warranted among Ashkenazi Jewish couples. 相似文献
7.
Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency 总被引:4,自引:0,他引:4 下载免费PDF全文
Huizing M Anikster Y Fitzpatrick DL Jeong AB D'Souza M Rausche M Toro JR Kaiser-Kupfer MI White JG Gahl WA 《American journal of human genetics》2001,69(5):1022-1032
Hermansky-Pudlak syndrome (HPS), consisting of oculocutaneous albinism and a bleeding diathesis due to the absence of platelet dense granules, displays extensive locus heterogeneity. HPS1 mutations cause HPS-1 disease, and ADTB3A mutations cause HPS-2 disease, which is known to involve abnormal intracellular vesicle formation. A third HPS-causing gene, HPS3, was recently identified on the basis of homozygosity mapping of a genetic isolate of HPS in central Puerto Rico. We now describe the clinical and molecular characteristics of eight patients with HPS-3 who are of non-Puerto Rican heritage. Five are Ashkenazi Jews; three of these are homozygous for a 1303+1G-->A splice-site mutation that causes skipping of exon 5, deleting an RsaI restriction site and decreasing the amounts of mRNA found on northern blotting. The other two are heterozygous for the 1303+1G-->A mutation and for either an 1831+2T-->G or a 2621-2A-->G splicing mutation. Of 235 anonymous Ashkenazi Jewish DNA samples, one was heterozygous for the 1303+1G-->A mutation. One seven-year-old boy of German/Swiss extraction was compound heterozygous for a 2729+1G-->C mutation, causing skipping of exon 14, and resulting in a C1329T missense (R396W), with decreased mRNA production. A 15-year-old Irish/English boy was heterozygous for an 89-bp insertion between exons 16 and 17 resulting from abnormal splicing; his fibroblast HPS3 mRNA is normal in amount but is increased in size. A 12-year-old girl of Puerto Rican and Italian background has the 3,904-bp founder deletion from central Puerto Rico on one allele. All eight patients have mild symptoms of HPS; two Jewish patients had received the diagnosis of ocular, rather than oculocutaneous, albinism. These findings expand the molecular diagnosis of HPS, provide a screening method for a mutation common among Jews, and suggest that other patients with mild hypopigmentation and decreased vision should be examined for HPS. 相似文献
8.
Vecsler M Ben Zeev B Nudelman I Anikster Y Simon AJ Amariglio N Rechavi G Baasov T Gak E 《PloS one》2011,6(6):e20733
Background
Nonsense mutations in the X-linked methyl CpG-binding protein 2 (MECP2) comprise a significant proportion of causative MECP2 mutations in Rett syndrome (RTT). Naturally occurring aminoglycosides, such as gentamicin, have been shown to enable partial suppression of nonsense mutations related to several human genetic disorders, however, their clinical applicability has been compromised by parallel findings of severe toxic effects. Recently developed synthetic NB aminoglycosides have demonstrated significantly improved effects compared to gentamicin evident in substantially higher suppression and reduced acute toxicity in vitro.Results
We performed comparative study of suppression effects of the novel NB54 and gentamicin on three MECP2 nonsense mutations (R294X, R270X and R168X) common in RTT, using ex vivo treatment of primary fibroblasts from RTT patients harboring these mutations and testing for the C-terminal containing full-length MeCP2. We observed that NB54 induces dose-dependent suppression of MECP2 nonsense mutations more efficiently than gentamicin, which was evident at concentrations as low as 50 µg/ml. NB54 read-through activity was mutation specific, with maximal full-length MeCP2 recovery in R168X (38%), R270X (27%) and R294X (18%). In addition, the recovered MeCP2 was translocated to the cell nucleus and moreover led to parallel increase in one of the most important MeCP2 downstream effectors, the brain derived neurotrophic factor (BDNF).Conclusion
Our findings suggest that NB54 may induce restoration of the potentially functional MeCP2 in primary RTT fibroblasts and encourage further studies of NB54 and other rationally designed aminoglycoside derivatives as potential therapeutic agents for nonsense MECP2 mutations in RTT. 相似文献9.
Danit Oz-Levi Bruria Ben-Zeev Elizabeth K. Ruzzo Yuki Hitomi Amir Gelman Kimberly Pelak Yair Anikster Haike Reznik-Wolf Ifat Bar-Joseph Tsviya Olender Anna Alkelai Meira Weiss Edna Ben-Asher Dongliang Ge Kevin V. Shianna Zvulun Elazar David B. Goldstein Elon Pras Doron Lancet 《American journal of human genetics》2012
10.
Danit Oz-Levi Bruria Ben-Zeev Elizabeth?K. Ruzzo Yuki Hitomi Amir Gelman Kimberly Pelak Yair Anikster Haike Reznik-Wolf Ifat Bar-Joseph Tsviya Olender Anna Alkelai Meira Weiss Edna Ben-Asher Dongliang Ge Kevin?V. Shianna Zvulun Elazar David?B. Goldstein Elon Pras Doron Lancet 《American journal of human genetics》2012,91(6):1065-1072
We studied five individuals from three Jewish Bukharian families affected by an apparently autosomal-recessive form of hereditary spastic paraparesis accompanied by severe intellectual disability, fluctuating central hypoventilation, gastresophageal reflux disease, wake apnea, areflexia, and unique dysmorphic features. Exome sequencing identified one homozygous variant shared among all affected individuals and absent in controls: a 1 bp frameshift TECPR2 deletion leading to a premature stop codon and predicting significant degradation of the protein. TECPR2 has been reported as a positive regulator of autophagy. We thus examined the autophagy-related fate of two key autophagic proteins, SQSTM1 (p62) and MAP1LC3B (LC3), in skin fibroblasts of an affected individual, as compared to a healthy control, and found that both protein levels were decreased and that there was a more pronounced decrease in the lipidated form of LC3 (LC3II). siRNA knockdown of TECPR2 showed similar changes, consistent with aberrant autophagy. Our results are strengthened by the fact that autophagy dysfunction has been implicated in a number of other neurodegenerative diseases. The discovered TECPR2 mutation implicates autophagy, a central intracellular mechanism, in spastic paraparesis. 相似文献