共查询到20条相似文献,搜索用时 31 毫秒
1.
β-thalassemia mutations in the Portuguese population 总被引:2,自引:0,他引:2
M. P. Coutinho Gomes M. G. Gomes da Costa L. B. Braga N. T. Cordeiro-Ferreira A. Loi M. Pirastu A. Cao 《Human genetics》1988,78(1):13-15
Summary In this study we have carried out haplotype analysis on the -globin gene cluster and characterized the -thalassemia mutation by oligonucleotide hybridization in 14 patients with thalassemia major and 5 with sickle cell/-thalassemia originating from southern Portugal. We found that three mutations, namely the °-39, ° IVS-1 nt 1 and + IVS-1 nt 110 are prevalent accounting for 53%, 32% and 10% of the -thalassemia chromosomes respectively. In general each mutation was associated with a specific chromosomal haplotype; the ° mutation, however, was linked to three different haplotypes. These results indicate that three oligo-probes complementary to the most common mutations allow prenatal diagnosis by oligonucleotide analysis in 96% of the couples at risk of having offspring with thalassemia major in southern Portugal. 相似文献
2.
van Bon BW Gilissen C Grange DK Hennekam RC Kayserili H Engels H Reutter H Ostergaard JR Morava E Tsiakas K Isidor B Le Merrer M Eser M Wieskamp N de Vries P Steehouwer M Veltman JA Robertson SP Brunner HG de Vries BB Hoischen A 《American journal of human genetics》2012,90(6):1094-1101
Cantú syndrome is a rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. Using an exome-sequencing approach applied to one proband-parent trio and three unrelated single cases, we identified heterozygous mutations in ABCC9 in all probands. With the inclusion of the remaining cohort of ten individuals with Cantú syndrome, a total of eleven mutations in ABCC9 were found. The de novo occurrence in all six simplex cases in our cohort substantiates the presence of a dominant disease mechanism. All mutations were missense, and several mutations affect Arg1154. This mutation hot spot lies within the second type 1 transmembrane region of this ATP-binding cassette transporter protein, which may suggest an activating mutation. ABCC9 encodes the sulfonylurea receptor (SUR) that forms ATP-sensitive potassium channels (K(ATP) channels) originally shown in cardiac, skeletal, and smooth muscle. Previously, loss-of-function mutations in this gene have been associated with idiopathic dilated cardiomyopathy type 10 (CMD10). These findings identify the genetic basis of Cantú syndrome and suggest that this is a new member of the potassium channelopathies. 相似文献
3.
Somatic mutations of mitochondrial DNA have been detected in various pathologies such as cancer, neurodegenerative diseases,
cardiac disorders and aging in general. Now it has been found that patients with rheumatoid arthritis also have a higher incidence
of mitochondrial mutations in synoviocytes and synovial tissue compared with patients with osteoarthritis. Furthermore, it
has been shown that these mutations possibly result in changed peptides that are presented by major histocompatibility complex
II and thus might be recognized as non-self by the immune system. Further studies will show whether these mutations are actually
able to trigger autoimmune inflammation in rheumatoid arthritis or whether they must be considered epiphenomena of cellular
damage in chronic inflammation. 相似文献
4.
K. van Engelen A. V. Postma J. B. A. van de Meerakker J. W. Roos-Hesselink A. T. J. M. Helderman-van den Enden H. W. Vliegen T. Rahman M. J. H. Baars J-W Sels U. Bauer T. Pickardt S. R. Sperling A. F. M. Moorman B. Keavney J. Goodship S. Klaassen B. J. M. Mulder 《Netherlands heart journal》2013,21(3):113-117
Ebstein’s anomaly is a rare congenital heart malformation characterised by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. Associated abnormalities of left ventricular morphology and function including left ventricular noncompaction (LVNC) have been observed. An association between Ebstein’s anomaly with LVNC and mutations in the sarcomeric protein gene MYH7, encoding β-myosin heavy chain, has been shown by recent studies. This might represent a specific subtype of Ebstein’s anomaly with a Mendelian inheritance pattern. In this review we discuss the association of MYH7 mutations with Ebstein’s anomaly and LVNC and its implications for the clinical care for patients and their family members. 相似文献
5.
Intrinsically disordered proteins (IDPs) have been implicated in a number of human diseases, including cancer, diabetes, neurodegenerative and cardiovascular disorders. Although for some of these conditions molecular mechanisms are now better understood, the big picture connecting distinct structural properties and functional repertoire of IDPs to pathogenesis and disease progression is still incomplete. Recent studies suggest that signaling and regulatory roles carried out by IDPs require them to be tightly regulated, and that altered IDP abundance may lead to disease. Here, we propose another link between IDPs and disease that takes into account disease-associated missense mutations located in the intrinsically disordered regions. We argue that such mutations are more prevalent and have larger functional impact than previously thought. In addition, we demonstrate that deleterious amino acid substitutions that cause disorder-to-order transitions are particularly enriched among disease mutations compared to neutral polymorphisms. Finally, we discuss potential differences in functional outcomes between disease mutations in ordered and disordered regions, and challenge the conventional structure-centric view of missense mutations. 相似文献
6.
Compensatory evolution of pbp mutations restores the fitness cost imposed by β-lactam resistance in Streptococcus pneumoniae 总被引:1,自引:0,他引:1
The prevalence of antibiotic resistance genes in pathogenic bacteria is a major challenge to treating many infectious diseases. The spread of these genes is driven by the strong selection imposed by the use of antibacterial drugs. However, in the absence of drug selection, antibiotic resistance genes impose a fitness cost, which can be ameliorated by compensatory mutations. In Streptococcus pneumoniae, β-lactam resistance is caused by mutations in three penicillin-binding proteins, PBP1a, PBP2x, and PBP2b, all of which are implicated in cell wall synthesis and the cell division cycle. We found that the fitness cost and cell division defects conferred by pbp2b mutations (as determined by fitness competitive assays in vitro and in vivo and fluorescence microscopy) were fully compensated by the acquisition of pbp2x and pbp1a mutations, apparently by means of an increased stability and a consequent mislocalization of these protein mutants. Thus, these compensatory combinations of pbp mutant alleles resulted in an increase in the level and spectrum of β-lactam resistance. This report describes a direct correlation between antibiotic resistance increase and fitness cost compensation, both caused by the same gene mutations acquired by horizontal transfer. The clinical origin of the pbp mutations suggests that this intergenic compensatory process is involved in the persistence of β-lactam resistance among circulating strains. We propose that this compensatory mechanism is relevant for β-lactam resistance evolution in Streptococcus pneumoniae. 相似文献
7.
《Mutation Research/Genetic Toxicology》1978,58(1):23-27
4 furocoumarins, namely psoralen (P), 8-methoxypsoralen (8-MOP), 4,5′,8-trimethylpsoralen (TMP) and angelicin (A) were tested for dark mutagenesis in E. coli lac−. Three compounds; P, 8-MOP and A were shown to be weak frameshift mutagens. TMP, surprisingly in view of its very active photosensitizing action, was found to be non-mutagenic. These results are discussed in relation to the photosensitizing action of the furocoumarins. 相似文献
8.
Jean Muller C. Stoetzel M. C. Vincent C. C. Leitch V. Laurier J. M. Danse S. Hellé V. Marion V. Bennouna-Greene S. Vicaire A. Megarbane J. Kaplan V. Drouin-Garraud M. Hamdani S. Sigaudy C. Francannet J. Roume P. Bitoun A. Goldenberg N. Philip S. Odent J. Green M. Cossée E. E. Davis N. Katsanis D. Bonneau A. Verloes O. Poch J. L. Mandel H. Dollfus 《Human genetics》2010,127(5):583-593
Bardet–Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations. 相似文献
9.
Kapri-Pardes E Katz A Haviv H Mahmmoud Y Ilan M Khalfin-Penigel I Carmeli S Yarden O Karlish SJ 《The Journal of biological chemistry》2011,286(50):42888-42899
The α2 isoform of Na,K-ATPase plays a crucial role in Ca2+ handling, muscle contraction, and inotropic effects of cardiac glycosides. Thus, structural, functional, and pharmacological comparisons of α1, α2, and α3 are of great interest. In Pichia pastoris membranes expressing human α1β1, α2β1, and α3β1 isoforms, or using the purified isoform proteins, α2 is most easily inactivated by heating and detergent (α2 ≫ α3 > α1). We have examined an hypothesis that instability of α2 is caused by weak interactions with phosphatidylserine, which stabilizes the protein. Three residues, unique to α2, in trans-membrane segments M8 (Ala-920), M9 (Leu-955), and M10 (Val-981) were replaced by equivalent residues in α1, singly or together. Judged by the sensitivity of the purified proteins to heat, detergent, “affinity” for phosphatidylserine, and stabilization by FXYD1, the triple mutant (A920V/L955F/V981P, called α2VFP) has stability properties close to α1, although single mutants have only modest or insignificant effects. Functional differences between α1 and α2 are unaffected in α2VFP. A compound, 6-pentyl-2-pyrone, isolated from the marine fungus Trichoderma gamsii is a novel probe of specific phospholipid-protein interactions. 6-Pentyl-2-pyrone inactivates the isoforms in the order α2 ≫ α3 > α1, and α2VFP and FXYD1 protect the isoforms. In native rat heart sarcolemma membranes, which contain α1, α2, and α3 isoforms, a component attributable to α2 is the least stable. The data provide clear evidence for a specific phosphatidylserine binding pocket between M8, M9, and M10 and confirm that the instability of α2 is due to suboptimal interactions with phosphatidylserine. In physiological conditions, the instability of α2 may be important for its cellular regulatory functions. 相似文献
10.
11.
Is the occurrence of some spontaneous mutations directed by environmental challenges? 总被引:2,自引:0,他引:2
B G Hall 《The New biologist》1991,3(8):729-733
12.
Juan Dong Jenny Chang-Claude Yixin Wu Valérie Schumacher Irmgard Debatin Patricia Tonin Brigitte Royer-Pokora 《Human genetics》1998,103(2):154-161
We have analyzed 61 German breast and breast/ovarian cancer families for BRCA1 mutations using single-strand conformation
polymorphism analysis (SSCP) followed by sequencing. Forty-seven of the families had at least three cases (at least two under
60 years) and 14 families had only two cases of breast/ovarian cancer (at least one under 50 years). Twenty-eight families
were breast/ovarian and 33 were breast cancer-only families. Eighteen mutations in BRCA1 were detected in 11/28 breast/ovarian
cancer families and 7/33 breast cancer families and none in the families with only two cases. We identified 17 truncation
mutations (8 frameshift, 7 nonsense and 2 splice variants) and one missense mutation. Seven of these are novel and two, the
5382insC and 5622C→T mutations, occurred in two apparently unrelated families. The genotype of the two families with the 5382insC
mutation is compatible with the rare haplotype segregating with the 5382insC mutation in different populations, further supporting
its European origin. One unclassified missense alteration, R841W, was found in one family but did not segregate with the disease,
suggesting that it is more likely a polymorphism. We also report and discuss the sequence of several new unclassified single-nucleotide
changes first identified by SSCP. Of the 18 mutations, 13 occurred in the 3′ third of the gene (end of exon 11–24) and ovarian
cancers were found in eight of these families.
Received: 5 February 1998 / Accepted: 7 April 1998 相似文献
13.
Novel and recurrent mutations in the tyrosinase gene and the P gene in the German albino population 总被引:5,自引:0,他引:5
Albinism is a heterogeneous group of genetic disorders resulting from deficiencies in pigmentation. Clinically, it is divided into ocular (OA) and oculocutaneous albinism (OCA). OCA involves lack of pigment in the skin, hair, and eyes and results from mutations in the tyrosinase gene or in the P gene. OA mainly affects pigmentation in the visual system and may be a mild form of OCA or may be caused by other genetic defects. Clinical diagnosis of albinism type is difficult, because of the observed range of phenotypic variation. Thus, genetic analysis may be helpful with respect to a more accurate diagnosis. Here, we report the mutational profile, determined by genetic analysis of the tyrosinase and P genes, of a large German albino population. We have revealed a total of 42 distinct mutations, 19 of which are novel. Of the 74 unrelated patients screened, 32 (43%) had mutations in the tyrosinase gene, 16 (22%) had P gene mutations, and 26 (35%) patients had no detectable genetic abnormalities. This defines a population of albino patients who are tyrosinase-gene- and P-gene-negative and who thus may represent a good study group for searching for additional genes associated with albinism. 相似文献
14.
Wang Liang Chen Xusheng Wu Guangyao Li Shu Zeng Xin Ren Xidong Tang Lei Mao Zhonggui 《Bioprocess and biosystems engineering》2017,40(2):271-283
Bioprocess and Biosystems Engineering - ε-Poly-l-lysine (ε-PL), as a food additive, has been widely used in many countries. However, its production still needs to be improved. We... 相似文献
15.
Ashim C. Roy Wu-Xiang Liao Ying Chen Sabaratnam Arulkumaran Shan S. Ratnam 《Molecular and cellular biochemistry》1996,165(2):151-153
Seven new point mutations have been identified from LH -subunit gene by PCR-mediated SSCP, and sequencing. One mutation was found changing amino acid from Gln102 to Ser102. The remaining six mutations, which did not change the codings, were in complete linkage disequilibrium. SSCP can be used in the diagnosis of LH-related disorders. 相似文献
16.
Leo A. J. Kluijtmans Henk J. Blom Godfried H. J. Boers Bernard A. van Oost Frans J. M. Trijbels Lambert P. W. J. van den Heuvel 《Human genetics》1995,96(2):249-250
Direct sequencing of the coding region of the cystathionine -synthase (CBS) gene in two homocystinuric patients revealed the presence of two novel missense mutations. The first mutation, a 1111G A transition, resulted in the substitution of the evolutionary conserved valine-371 by a methionine residue (V371M) and created a new NlaIII restriction site. The second mutation, a GA transition at base-pair 494, resulted in an amino acid change from cysteine to tyrosine (C165Y) and abolished a BsoFI restriction site. Both mutations were found in a compound heterozygous state with the previously described 833T C transition. 相似文献
17.
A hallmark of Alzheimer's disease (AD) is the rearrangement of the β-amyloid (Aβ) peptide to a non-native conformation that promotes the formation of toxic, nanoscale aggregates. Recent studies have pointed to the role of sample preparation in creating polymorphic fibrillar species. One of many potential pathways for Aβ toxicity may be modulation of lipid membrane function on cellular surfaces. There are several mutations clustered around the central hydrophobic core of Aβ near the α-secretase cleavage site (E22G Arctic mutation, E22K Italian mutation, D23N Iowa mutation, and A21G Flemish mutation). These point mutations are associated with hereditary diseases ranging from almost pure cerebral amyloid angiopathy (CAA) to typical Alzheimer's disease pathology with plaques and tangles. We investigated how these point mutations alter Aβ aggregation in the presence of supported lipid membranes comprised of total brain lipid extract. Brain lipid extract bilayers were used as a physiologically relevant model of a neuronal cell surface. Intact lipid bilayers were exposed to predominantly monomeric preparations of Wild Type or different mutant forms of Aβ, and atomic force microscopy was used to monitor aggregate formation and morphology as well as bilayer integrity over a 12 hour period. The goal of this study was to determine how point mutations in Aβ, which alter peptide charge and hydrophobic character, influence interactions between Aβ and the lipid surface. While fibril morphology did not appear to be significantly altered when mutants were prepped similarly and incubated under free solution conditions, aggregation in the lipid membranes resulted in a variety of polymorphic aggregates in a mutation dependent manner. The mutant peptides also had a variable ability to disrupt bilayer integrity. 相似文献
18.
19.
X. J. Chen P. M. Hansbro G. D. Clark-Walker 《Molecular genetics and genomics : MGG》1998,259(5):457-467
Specific mgi mutations in the α, β or γ subunits of the mitochondrial F1-ATPase have previously been found to suppress ρ0 lethality in the petite-negative yeast Kluyveromyces lactis. To determine whether the suppressive activity of the altered F1 is dependent on the F0 sector of ATP synthase, we isolated and disrupted the genes KlATP4, 5 and 7, the three nuclear genes encoding subunits b, OSCP and d. Strains disrupted for any one, or all three of these genes are respiration deficient and have reduced viability. However a strain devoid of the three nuclear genes is still unable to lose mitochondrial DNA, whereas a mgi mutant with the three genes inactivated remains petite-positive. In the latter case, ρ0 mutants can be isolated, upon treatment with ethidium bromide, that lack six major F0 subunits, namely the nucleus-encoded subunits b, OSCP and d, and the mitochondrially encoded Atp6, 8 and 9p. Production of ρ0 mutants indicates that an F1-complex carrying a mgi mutation can assemble in the absence of F0 subunits and that suppression of ρ0 lethality is an intrinsic property of the altered F1 particle. 相似文献
20.