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Congenital end-plate acetylcholinesterase deficiency caused by a nonsense mutation and an A-->G splice-donor-site mutation at position +3 of the collagenlike-tail-subunit gene (COLQ): how does G at position +3 result in aberrant splicing?
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K Ohno J M Brengman K J Felice D R Cornblath A G Engel 《American journal of human genetics》1999,65(3):635-644
Congenital end-plate acetylcholinesterase (AChE) deficiency (CEAD), the cause of a disabling myasthenic syndrome, arises from defects in the COLQ gene, which encodes the AChE triple-helical collagenlike-tail subunit that anchors catalytic subunits of AChE to the synaptic basal lamina. Here we describe a patient with CEAD with a nonsense mutation (R315X) and a splice-donor-site mutation at position +3 of intron 16 (IVS16+3A-->G) of COLQ. Because both A and G are consensus nucleotides at the +3 position of splice-donor sites, we constructed a minigene that spans exons 15-17 and harbors IVS16+3A-->G for expression in COS cells. We found that the mutation causes skipping of exon 16. The mutant splice-donor site of intron 16 harbors five discordant nucleotides (at -3, -2, +3, +4, and +6) that do not base-pair with U1 small-nuclear RNA (snRNA), the molecule responsible for splice-donor-site recognition. Versions of the minigene harboring, at either +4 or +6, nucleotides complementary to U1 snRNA restore normal splicing. Analysis of 1,801 native splice-donor sites reveals that presence of a G nucleotide at +3 is associated with preferential usage, at positions +4 to +6, of nucleotides concordant to U1 snRNA. Analysis of 11 disease-associated IVS+3A-->G mutations indicates that, on average, two of three nucleotides at positions +4 to +6 fail to base-pair, and that the nucleotide at +4 never base-pairs, with U1 snRNA. We conclude that, with G at +3, normal splicing generally depends on the concordance that residues at +4 to +6 have with U1 snRNA, but other cis-acting elements may also be important in assuring the fidelity of splicing. 相似文献
3.
Massoud Houshmand Nils-Göran Larsson Anders Oldfors Már Tulinius Elisabeth Holme 《Human genetics》1996,97(3):269-273
A girl, who died at 14 years of age from a rapidly progressive mitochondrial myopathy, was found to be heteroplasmic for a mutation in the mitochondrial tRNALeu(UUR) gene at position 3251. A large proportion of muscle fibres contained accumulations of abnormal mitochondria but no cytochrome c oxidase deficient fibres were present. Polarographic and enzymatic measurements on isolated muscle mitochondria revealed a profound isolated complex I deficiency. A high percentage of mutant mtDNA was found in muscle (94%), fibroblasts (93%), brain (90%), liver (80%), and heart (79%). The family was not available for investigation. For genotype to phenotype correlation studies, we investigated the proportion of mutated mtDNA in single muscle fibres of normal appearance and muscle fibres with accumulations of mitochondria. The proportion of mutant mtDNA was 28% (range < 0.3%–86%) in normal-appearing fibres and 61% (range 15%–88%) in abnormal fibres. The difference in the proportion of mutant mtDNA was highly significant (P < 0.001) between the two groups of fibres. 相似文献
4.
The relationship between the phenotype and the genotype is complex in diseases caused by mutations in mitochondrial DNA (mtDNA). The 3243A-->G mutation in mtDNA frequently leads to sensorineural hearing impairment (HI), a phenotype that can be assessed in severity by audiometry; hence, consecutive audiograms can give an estimate of the rate of HI progression.We examined the audiological phenotype of 38 patients (14 men, 24 women; mean age: 45+/-14 years) who possessed the 3243A-->G mutation and who belonged to a population-based cohort ascertained in the province of Northern Ostrobothnia, Finland. The subjects took part in an otorhinolaryngologic examination, including audiometry. Factors modulating the severity of HI were analyzed, and the rate of HI progression was calculated. The better ear hearing level (BEHL) at frequencies 0.5, 1, 2, and 4 kHz (BEHL0.5-4kHz) was greater than 20 dB suggesting HI in 28 patients (74%). A good correlation (r=0.428, P=0.009) was found between BEHL0.5-4kHz and the degree of the mutant heteroplasmy. BEHL0.5-4kHz was worse in men than in women, and women outnumbered men among patients with normal hearing or mild HI. In addition, 181 consecutive audiograms were reviewed from 24 patients with HI. The rate of HI progression was calculated to be 2.9 dB/year in men and 1.5 dB/year in women, being clearly faster than the rates that have been observed in the corresponding age group in the general population. A high degree of mutant heteroplasmy, male gender, and age were found to increase the severity of HI. Phenotypic difference by gender may thus be a more universal phenomenon in mitochondrial diseases, not only being associated with Leber's hereditary optic neuropathy. This study provides the first estimate of the rate of disease progression among patients with the 3243A-->G mutation. 相似文献
5.
Endomyces fibuliger is a dimorphic yeast which is homothallic and exists predominantly in the diploid phase with a brief haploid
phase. A repeat unit of the ribosomal RNA genes, or rDNA, from E. fibuliger 8014 met has been isolated, cloned and sequenced.
In this report, the sequences of the 17S, 5.8S and 26S rRNA genes are presented. Homology between the sequenced rRNA genes
and those of closely-related yeast strains, particularly Saccharomyes cerevisiae and Candida albicans, was observed. As a
step towards the eventual development of a transformation system for the yeast E. fibuliger, an integrative plasmid containing
the 5.8S and a part of the 26S rRNA gene, a selectable marker conferring resistance to the G418 antibiotic and a reporter
gene, the α-amylase (ALP1) gene of E. fibuliger, was constructed. This plasmid was linearized at a unique restriction site
within the 26S rRNA gene, and transformed into S. cerevisiae INVSC2 MATa his3 ura3 using the lithium acetate method to test
the functionality of the vector system. Transformation into S. cerevisiae INVSC2 MATa his3 ura3 was by virtue of the extensive
homology between the sequenced 26S rRNA gene of E. fibuliger 8014 met and that of S. cerevisiae, so that homologous pairing
and integration into the recipient chromosome was possible. The G418-resistant S. cerevisiae transformants produced halos
on starch medium due to hydrolysis by α-amylase, and they were further analysed by Southern hybridization with the ALP1 gene
and the gene encoding the aminoglycoside 3′- phosphotransferase I enzyme which confers resistance to the G418 antibiotic.
A band of 13.7 kb which corresponded to the linearized size of the transforming plasmid DNA was obtained on the autoradiogram,
suggesting that tandem copies of the plasmid DNA are present in the chromosome. Finally, an assay of the α-amylase enzyme
secreted extracellularly was performed on the transformants. 相似文献
6.
M. Todd Tippetts Donald L. Robertson Marvin A. Smith 《Molecular and cellular biochemistry》1991,100(1):61-70
Summary A recombinant DNA library was constructed from partial BamHI or MboI digests of safflower (Carthamus tinctorius L.) chloroplast DNA, in the BamHI site of EMBL3. Seventeen recombinants, selected by chromosome walking, were found to contain overlapping fragments of the entire chloroplast genome. These clones were mapped using single and double digests of BamHI, EcoRI and HindIII. cDNAs synthesized from isolated 16S and 23S chloroplast rRNAs were used to map the ribosomal RNA genes relative to physical maps of the above restriction enzymes. The mapped positions of the rRNA genes for the safflower chloroplast DNA are in good agreement with previously published data for tobacco, spinach and several other higher plants. 相似文献
7.
Haruko Takeda Carole Charlier Frédéric Farnir Michel Georges 《RNA (New York, N.Y.)》2010,16(9):1854-1863
We herein describe the development of a biochemical method to evaluate the effect of single nucleotide polymorphisms (SNPs) in target genes on their regulation by microRNAs in vivo. The method is based on the detection of allelic imbalance in RNAs coimmunoprecipitated with AGO proteins from tissues of heterozygous individuals. We characterize the performances of our approach using a model system in a cell culture, and then apply it successfully to prove that the 3′UTR g+6223G→A mutation operates by promoting RISC-dependent down-regulation of myostatin (MSTN) in skeletal muscle of Texel sheep. 相似文献
8.
Meiheng Yang Howard Allen Hisao Fukushima Richard A. DiCioccio 《Glycoconjugate journal》1984,1(1):15-19
Fucosidosis is an autosomal recessive lysosomal storage disease resulting from the absence of -l-fucosidase activity. Two natural missense mutations (G197A) and (A860G) within the -l-fucosidase gene have been reported to be homozygous in four patients with fucosidosis. Expression of wild-type and mutated -l-fucosidase cDNAs in COS-1 cells revealed complete deficiency of -l-fucosidase for the G197A transition and a normal level of enzyme for A860G. We therefore conclude that the change of G197A is responsible for fucosidosis in the patients while A860G is a normal polymorphic variant of -l-fucosidase. 相似文献
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Xinfeng Liu Hanlu Fan Xiangbin Ding Zhongshan Hong Yongwei Nei Zhongwei Liu Guangpeng Li Hong Guo 《Current microbiology》2014,68(5):657-662
Considerable evidence suggests that the gut microbiota is complex in many mammals and gut bacteria communities are essential for maintaining gut homeostasis. To date the research on the gut microbiota of donkey is surprisingly scarce. Therefore, we performed high-throughput sequencing of the 16S rRNA genes V5–V6 hypervariable regions from gut fecal material to characterize the gut microbiota of healthy donkeys and compare the difference of gut microbiota between male and female donkeys. Sixty healthy donkeys (30 males and 30 females) were enrolled in the study, a total of 915,691 validated reads were obtained, and the bacteria found belonged to 21 phyla and 183 genera. At the phylum level, the bacterial community composition was similar for the male and female donkeys and predominated by Firmicutes (64 % males and 64 % females) and Bacteroidetes (23 % males and 21 % females), followed by Verrucomicrobia, Euryarchaeota, Spirochaetes, and Proteobacteria. At the genus level, Akkermansia was the most abundant genus (23 % males and 17 % females), followed by Sporobacter, Methanobrevibacter, and Treponema, detected in higher distribution proportion in males than in females. On the contrary, Acinetobacter and Lysinibacillus were lower in males than in females. In addition, six phyla and 15 genera were significantly different between the male and female donkeys for species abundance. These findings provide previously unknown information about the gut microbiota of donkeys and also provide a foundation for future investigations of gut bacterial factors that may influence the development and progression of gastrointestinal disease in donkey and other animals. 相似文献
11.
《生物化学与生物物理学报:疾病的分子基础》2000,1500(1):10-16
The MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) is most commonly caused by the 3243A→G mutation in mitochondrial DNA, resulting in impaired mitochondrial protein synthesis and decreased activities of the respiratory chain complexes. These defects may cause a reduced capacity for ATP synthesis and an increased rate of production of reactive oxygen species. Myoblasts cultured from controls and patients carrying the 3243A→G mutation were used to measure ATP, ADP, catalase and superoxide dismutase, which was also measured from blood samples. ATP and ADP concentrations were decreased in myoblasts with the 3243A→G mutation, but the ATP/ADP ratio remained constant, suggesting a decrease in the adenylate pool. The superoxide dismutase and catalase activities were higher than in control cells, and superoxide dismutase activity was slightly, but not significantly higher in the blood of patients with the mutation than in controls. We conclude that impairment of mitochondrial ATP production in myoblasts carrying the 3243A→G mutation results in adenylate catabolism, causing a decrease in the total adenylate pool. The increase in superoxide dismutase and catalase activities could be an adaptive response to increased production of reactive oxygen species due to dysfunction of the mitochondrial respiratory chain. 相似文献
12.
M. Al-Ani S. M. Munir M. White J. Townend J. H. Coote 《European journal of applied physiology and occupational physiology》1996,74(5):397-403
The long-term conditioning effects of physical training on cardiorespiratory interaction in 11 young healthy males were studied.
Significant increases in maximum oxygen uptake (V˙O2max)(P<0.05) and decreases in heart rate (P<0.05) were achieved in all subjects following a 6-week training programme consisting of cycling for 25min each day at a work
level that increased heart rate to 85% of maximum. Heart rate variability, measured as the differences between the maximum
and minimum R–R interval in a respiratory cycle, increased in nine of the subjects and decreased in two. The respiratory-cycle-related
high-frequency peak in the power spectral plot of R–R variability also showed significant increases in the same nine subjects
and decreases in two. The latter result was similar after normalisation of the data for changes in heart rate by calculating
the common coefficient of variance (CCV=HFR–R×<∮∮), where HF is the high-frequency component of the power spectral plots,
using a further measure of vagal tone it was shown that, for all subjects, the R–R interval change in response to isometric
contractions of the arm flexors in one respiratory cycle were significantly greater after training. These data suggest that
cardiac vagal tone is increased by aerobic training for all subjects and that this is accompanied by a respiratory sinus arrhythmia
(RSA) in most, but may be associated with a decrease in RSA in subjects with a very low (< 50 beats⋅min-1 heart rate.
Accepted: 23 April 1996 相似文献
13.
Ujan JA Zan LS Ujan SA Adoligbe C Wang HB 《Genetics and molecular research : GMR》2011,10(4):3070-3079
Qualitative trait loci (QTL) for growth and meat quality traits in cattle (Bos taurus) have been previously mapped to three chromosome regions, 0 to 30, 55 to 70, and 70 to 80 cM on chromosome 5. We evaluated the allele frequencies and gene-specific single nucleotide polymorphisms (SNPs) of bovine myogenic factor 5 (MyF-5) in the QTL regions and their associations with live weight and meat characteristics in indigenous Chinese cattle breeds. PCR-SSCP methodology showed a T>A mutation at 526 bp. Least square analysis revealed a significant association of this SNP with backfat thickness and meat tenderness (P < 0.05), while no significant association was found with live weight, loin eye height, loin eye area, rib area, or water holding capacity. Allele frequencies of MyF-5-A/B in the five breeds were 0.760/0.239, 0.752/0.247, 0.629/0.370, 0.715/0.284, and 0.750/0.250, for JiaXian red, Luxi, Nanyang, Qinchuan, and XiaNan crossbreed, respectively. The genotype distributions for these alleles in two of the Chinese cattle breeds (Luxi and Qinchuan) were not in Hardy-Weinberg equilibrium (P < 0.05); while those for the other three breeds (JiaXian red, Nanyang, and XiaNan) were in agreement with Hardy-Weinberg equilibrium (P > 0.05). The genotypic frequencies among all five cattle breeds showed moderate diversity (0.25 < polymorphism information content < 0.5). Based on our findings, we suggest that the MyF-5 gene influences back fat thickness and meat tenderness in Chinese Bos taurus. This SNP could be useful for marker-assisted selection for meat quality traits in these cattle. 相似文献
14.
Maria Tzetis Alexandra Efthymiadou Stavros Doudounakis Emmanuel Kanavakis 《Human genetics》2001,109(6):592-601
15.
O'connor M 《Molecular genetics and genomics : MGG》2007,278(3):307-315
A1916 in 23S rRNA is located in one of the major intersubunit bridges of the 70S ribosome. Deletion of A1916 disrupts the
intersubunit bridge B2a, promotes misreading of the genetic code and is lethal. In a genetic selection for suppressor mutations,
two base substitutions in 16S rRNA were recovered that restored viability and also allowed expression of ΔA1916-associated
capreomycin resistance. These mutations were G1048A in helix 34 and U1471C in helix 44. Restoration of function is incomplete,
however, and the double mutants are slow-growing, defective in subunit association and support high levels of translational
errors. In contrast, none of these parameters is affected by the single 16S suppressor mutations. U1471C likely affects another
intersubunit contact, bridge B6, suggesting that interactions between different bridges and cross-talk between subunits contributes
to ribosomal function. 相似文献
16.
《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2001,761(1):47-60
The results of a validation study of a GC–NCI–MS method for the quantitative determination of 5-nitroimidazoles {1,2-Dimethyl-5-nitroimidazole (dimetridazole, DMZ), 1-methyl-2-[(carbamoyloxy)methyl]-5-nitroimidazole (ronidazole, RNZ), 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole (metronidazole, MNZ) and 2-isopropyl-1-methyl-5-nitroimidazole (ipronidazole, IPZ)} including the hydroxy metabolites of these agents {2-hydroxymethyl-1-methyl-5-nitroimidazole (HMMNI), 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole (MNZOH), and 1-methyl-2-(2′-hydroxyisopropyl)-5-nitroimidazole (IPZOH)} in turkey and swine muscle are presented. The validation was carried out according to the requirements of the draft for the revision of Commission Decision 93/256/EC, which is expected to be adopted by the European Commission in due course. The determination of the method’s performance parameters revealed decision limits (CCα) between 0.65 and 2.8 μg/kg for DMZ, RNZ/HMMNI, MNZ and MNZOH. Confirmatory analyses according to the requirements of the forthcoming EC decision are possible for all analytes except for IPZ and IPZOH where already the decision limits (CCα) were higher (5.2 μg/kg) than for the above-mentioned nitroimidazoles. The within-laboratory reproducibility and the mean recovery were in an acceptable range for all analytes. 相似文献
17.
Charlene J. Williams Eileen L. Considine Robert G. Knowlton Antonio Reginato Guillermo Neumann David Harrison Paul Buxton Sergio Jimenez Darwin J. Prockop 《Human genetics》1993,92(5):499-505
Direct sequencing of polymerase chain reaction (PCR)-amplified genomic DNA from a patient with spondyloepiphyseal dysplasia and precocious osteoarthritis revealed a single-base change in exon 11 of the type II procollagen gene (COL2A1), which produces an Arg Cys mutation in one allele. The proband is a member of a large Chilean kindred presenting with chondrodysplasia of the hips, knees, shoulders, elbows, and spine associated with severe, early-onset osteoarthritis. All affected individuals exhibit mildly short stature; in addition, five out of seven affected family members display shortened metacarpals or metatarsals. DNA from affected and unaffected family members was PCR-amplified and analysis of restriction digests of the products determined that the mutation segregated with the disease with a lod score of 2.2 at zero recombination. The mutation, which resides in the triple-helical region of type II procollagen at amino acid position 75, is the second example of an ArgCys mutation in the COL2A1 gene in heritable cartilaginous disease and is the first example of a point mutation in the amino terminal region of the 1(II) chain, that results in a spondyloepiphyseal dysplastic phenotype. 相似文献
18.
In this review, the validity of evolutionary conclusions inferred from the quantitative estimates of the similarity between bacterial genes is evaluated using the order Halonanaerobiales as an example. The haloanaerobic phenotype is briefly characterized, as are some specific features that allow the order Haloanaerobiales to serve as a reference taxon. Phylogenetic analysis provides a set of standard quantitative criteria for ranking bacterial taxa from species to families. Recommendations for the use of these standard criteria are given. 相似文献
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Sorahia Domenice Miriam Yumie Nishi Ana Elisa Correia Billerbeck Ana Claudia Latronico Maria Aparecida Medeiros Alan John Russell Keith Vass Filomena Marino Carvalho Elaine Maria Costa Frade Ivo Jorge Prado Arnhold B. Bilharinho Mendonca 《Human genetics》1998,102(2):213-215
Mutations in the sex-determining region of the Y chromosome (the SRY gene) have been reported in low frequency in patients
with 46,XY gonadal dysgenesis. We investigated 21 Brazilian 46,XY sex-reversed patients, who presented either complete or
partial gonadal dysgenesis or embryonic testicular regression syndrome. Using Southern blotting, polymerase chain reaction,
denaturing gradient gel electrophoresis and direct sequencing, we analyzed deletions and point mutations in the SRY gene.
We found a missense mutation at codon 18 upstream of the 5′ border of the HMG box of the SRY gene in one patient with partial
gonadal dysgenesis. This variant sequence was also found in DNA obtained from blood and sperm cells of his father and in blood
cells of his normal brother. The S18N mutation was not found in 50 normal males, ruling out the possibility of a common polymorphism.
We identified a novel familial missense mutation (S18N) in the 5’ non-HMG box of the SRY gene in 1 of 21 patients with 46,XY
sex reversal.
Received: 6 May 1997 / Accepted: 2 October 1997 相似文献