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1.
Maryse Bonduelle Willy Lissens Anne Malfroot Isi Dab Inge Liebaers 《Human genetics》1990,85(4):395-396
Summary The cystic fibrosis (CF) gene deletion F508 was studied in a Belgian population of 74 families and their 83 CF children. The
haplotypes for CF and normal chromosomes had previously been determined with several linked DNA probes. In our CF population,
the gene deletion F508 was found in 76% of the mutant alleles. Of the deletion F508, 97% segregated with the highest risk
haplotype for the CF carrier status. Some 61% of our families were found to be homozygous for this major CF mutation. Each
of our three pancreatic sufficiency patients (two of whom were siblings) was heterozygote for the F508 deletion. 相似文献
2.
I. Lerer S. Cohen M. Chemke A. Sanilevich J. Rivlin A. Golan J. Yahav A. Friedman D. Abeliovich 《Human genetics》1990,85(4):416-417
Summary We have analysed the distribution of the ΔF508 mutation and the haplotypes of cystic fibrosis (CF) bearing chromosomes among
the Israeli CF population. The population was classified according to its ethnic origin and included 3 groups, Ashkenazi Jews,
Sephardic/Oriental Jews and Arabs. Haplotype B (KM19 allele 2, XV2c allele 1) was found to be the predominant haplotype in
all groups but in each of them the haplotype distribution was different. The ΔF508 mutation was present in all groups and
accounts for 32% of the CF mutations. It was mainly associated with the B haplotype but only one third of the CF chromosomes
with this haplotype carry the ΔF508 mutation.
This work is dedicated to Dr. Ruth Voss who initiated the CF study in Israel and was tragically killed in a car accident on
7 August 1988 相似文献
3.
Cystic fibrosis typing with DNA probes and screening for ΔF508 deletion in families from Southern France 总被引:1,自引:1,他引:0
Mireille Claustres Marie Desgeorges Paule Kjellherg Hélène Bellet Jacques Demaille Michelle Ramsay 《Human genetics》1990,85(4):398-399
Summary A sample of 235 individuals from 49 French cystic fibrosis (CF) families with at least one living affected child was typed
with probes for restriction fragment length polymorphisms (RFLPs) known to be linked to the CF gene, and was screened for
the ΔF508 mutation. Using a combination of six probes, 44 out of the 49 families were sufficiently informative to enable prenatal
diagnosis or carrier determination. As in many other populations, linkage disequilibrium was found between the CF locus and
the haplotype B (XV2c: allele 1; KM19: allele 2), which accounts for about 78% of CF chromosomes in our families. The ΔF508
deletion was present in 64.3% of CF chromosomes. 相似文献
4.
Harry Cuppens Eric egius Pablo Cabello Peter Marynen Chris De Boeck Ronny Decorte Jean-Pierre Fryns Ephraim Eggermont Herman Van den Berghe Jean-Jacques Cassiman 《Human genetics》1990,85(4):402-403
Summary Using Southern blotting and the polymerase chain reaction, the prevalence of the haplotypes for XV2c, CS7, KM19 and D9 on
CF and on normal chromosomes could be determined in 35 Belgian families. A set of primers complementary to the DNA sequence
of the CF gene around the ΔF508 deletion was used to amplify this particular segment of the gene. In a total of 57 families,
deletion screening showed that 69 out of 116 CF chromosomes (59.5%) carried the ΔF508 deletion. Both the ΔF508 deletion and
another mutation(s) showed strong association with the haplotype 1-2-2-2. 相似文献
5.
Luborodna Kalaydjieva Jordan Antov Juliana Bronzova Violeta Vladimirova Jürgen Horst 《Human genetics》1990,85(4):412-413
Summary A group of 42 cystic fibrosis (CF) patients and 80 heterozygote carriers was analysed for determining the prevalent CF haplotypes
and the frequency of ΔF508. The “high-risk” haplotype B (XV2c-KM19/1 2) was found in 66% of CF chromosomes. The prevalent
normal haplotypes were A (1 1) and B (2 1). The deletion was detected in 54 CF chromosomes (56%), homozygotes constituting
35% of all CF patients. In 88% of cases the mutation was linked to haplotype B, and in 12% to haplotype D (2 2). Chromosomes
that did not have ΔF508 were found to be evenly distributed among all four XV2c-KM19 haplotypes. The use of restriction fragment
length polymorphisms and direct detection of the mutation makes 94% of CF families fully informative for prenatal analysis. 相似文献
6.
Alessandro Luciani Valeria Rachela Villella Speranza Esposito Manuela Gavina Ilaria Russo Marco Silano Stefano Guido Massimo Pettoello-Mantovani Rosa Carnuccio Bob Scholte Antonella De Matteis Maria Chiara Maiuri Valeria Raia Alberto Luini Guido Kroemer Luigi Maiuri 《Autophagy》2012,8(11):1657-1672
Channel activators (potentiators) of cystic fibrosis (CF) transmembrane conductance regulator (CFTR), can be used for the treatment of the small subset of CF patients that carry plasma membrane-resident CFTR mutants. However, approximately 90% of CF patients carry the misfolded ΔF508-CFTR and are poorly responsive to potentiators, because ΔF508-CFTR is intrinsically unstable at the plasma membrane (PM) even if rescued by pharmacological correctors. We have demonstrated that human and mouse CF airways are autophagy deficient due to functional sequestration of BECN1 and that the tissue transglutaminase-2 inhibitor, cystamine, or antioxidants restore BECN1-dependent autophagy and reduce SQSTM1/p62 levels, thus favoring ΔF508-CFTR trafficking to the epithelial surface. Here, we investigated whether these treatments could facilitate the beneficial action of potentiators on ΔF508-CFTR homozygous airways. Cystamine or the superoxide dismutase (SOD)/catalase-mimetic EUK-134 stabilized ΔF508-CFTR at the plasma membrane of airway epithelial cells and sustained the expression of CFTR at the epithelial surface well beyond drug withdrawal, overexpressing BECN1 and depleting SQSTM1. This facilitates the beneficial action of potentiators in controlling inflammation in ex vivo ΔF508-CFTR homozygous human nasal biopsies and in vivo in mouse ΔF508-CFTR lungs. Direct depletion of Sqstm1 by shRNAs in vivo in ΔF508-CFTR mice synergized with potentiators in sustaining surface CFTR expression and suppressing inflammation. Cystamine pre-treatment restored ΔF508-CFTR response to the CFTR potentiators genistein, Vrx-532 or Vrx-770 in freshly isolated brushed nasal epithelial cells from ΔF508-CFTR homozygous patients. These findings delineate a novel therapeutic strategy for the treatment of CF patients with the ΔF508-CFTR mutation in which patients are first treated with cystamine and subsequently pulsed with CFTR potentiators. 相似文献
7.
M. De Braekeleer Christian Allard Jean-Pierre Leblanc Fernand Simard Gervais Aubin 《Human genetics》1997,101(2):208-211
Cystic fibrosis (CF) has a high incidence in the French-Canadian population of Saguenay Lac-Saint-Jean (Quebec). The A455E
mutation accounts for 8.3% of the CF chromosomes. This mutation was shown to be associated with a milder lung disease in the
Dutch population. Twenty two CF patients distributed in 17 families and compound heterozygotes for the A455E mutation have
been followed at the Clinique de Fibrose Kystique de Chicoutimi. Fourteen patients also carried the ΔF508 mutation while the
remaining eight patients had the 621+ 1G→T mutation. Each patient was matched by sex and age to a patient homozygous for the
ΔF508 mutation. The pairs were analyzed for several clinical and laboratory variables. The A455E compound heterozygotes were
diagnosed at a later age (P = 0.003) and had chloride concentrations at the sweat test lower than those homozygous for the ΔF508 mutation (P = 0.007). More patients were pancreatic sufficient (P = 0.004). They had a higher Shwachman score (P = 0.001) and better pulmonary function tests (P < 0.02). CF patients compound heterozygous for the A455E mutation have a milder pancreatic and lung disease than the ΔF508
homozygotes. Therefore, the A455E should be associated with a better prognosis.
Received: 24 February 1997 / Accepted: 16 June 1997 相似文献
8.
Giuseppe Novelli Paolo Gasparini Anna Savoia Pier Franco Pignatti Federica Sangiuolo Bruno Dallapiccola 《Human genetics》1990,85(4):420-421
Summary Haplotype data based on the DNA markers closely linked to the cystic fibrosis (CF) gene have been used to correlate the presence
of the 3 by specific deletion (ΔF508) in 424 CF chromosomes from 212 Italian CF families. The distribution and the frequency
of the F508 deletion on CF chromosomes in our sample suggests the presence of at least a second mutation in the same ancestral
haplotype. 相似文献
9.
Theresa A. Grebe William K. Seltzer Jean DeMarchi Dinithi K. Silva W. W. Doane David Gozal S. F. Richter C. Michael Bowman R. A. Norman Susan N. Rhodes Lucy S. Hernried Shirley Murphy Ivan R. Harwood Frank J. Accurso Karen D. Jain 《American journal of human genetics》1994,54(3):443-446
We have performed molecular genetic analyses of Hispanic individuals with cystic fibrosis (CF) in the southwestern United States. Of 129 CF chromosomes analyzed, only 46% (59/129) carry ΔF508. The G542X mutation was found on 5% (7/129) of CF chromosomes. The 3849+10kbC→T mutation, detected primarily in Ashkenazi Jews, was present on 2% (3/129). R1162X and R334W, mutations identified in Spain and Italy, each occurred on 1.6% (2/129) of CF chromosomes. W1282X and R553X were each detected once. G551D and N1303K were not found. Overall, screening for 22 or more mutations resulted in detection of only 58% of CF transmembrane conductance regulator gene mutations among Hispanic individuals. Analysis of KM19/XV2c haplotypes revealed an unusual distribution. Although the majority of ΔF508 mutations are on chromosomes of B haplotypes, the other CF mutations are on A and C haplotypes at higher-than-expected frequencies. These genetic analyses demonstrate significant differences between Hispanic individuals with CF and those of the general North American population. Assessment of carrier/affected risk in Hispanic CF individuals cannot, therefore, be based on the mutation frequencies found through studies of the general population but must be adjusted to better reflect the genetic makeup of this ethnic group. Further studies are necessary to identify the causative mutation(s) in this population and to better delineate genotype/phenotype correlations. These will enable counselors to provide more accurate genetic counseling. 相似文献
10.
G. Restagno S. Garnerone C. Gennaro O. Varetto N. Ansaldi D. Castello B. Santini A. O. Carbonara 《Human genetics》1990,85(4):422-423
Summary In 20 Italian families with cystic fibrosis (CF), restriction fragment length polymorphisms were detected by five linked markers;
a strong linkage disequilibrium is observed between the haplotype B (alleles 2/1 with respect to KM19/XV2c) and CF. The frequency
of the ΔF508 deletion in CF chromosomes of this sample is 50%. A significant correlation is found between the absence of the
ΔF508 mutation and pancreatic sufficiency. 相似文献
11.
Juha Kere Erkki Savilahti Reijo Norio Xavier Estivill Albert de la Chapelle 《Human genetics》1990,85(4):413-415
Summary The frequency of mutation ΔF508 was determined in all 20 Finnish cystic fibrosis (CF) families with living affected children
(19 with pancreatic insufficiency). ΔF508 was detected in 18 out of 40 CF chromosomes (45%). At least two different mutations
associated with pancreatic insufficiently have occurred in a rare haplotype defined by XV2c, CS.7, KM19 alleles 1 2 2. Geographical
clustering of ΔF508 and other mutations suggested that a founder effect and genetic drift have influenced the frequency of
mutations causing CF in Finland. 相似文献
12.
M. Chillón V. Nunes T. Casals F. J. Giménez E. Fernández J. Benítez X. Estivill 《Human genetics》1990,85(4):396-397
Summary Spanish cystic fibrosis (CF) families (n = 194) have been analysed for the ΔF508 mutation, and for closely linked DNA markers. The ΔF508 mutation accounts for 50%
of CF chromosomes. Four haplotypes are associated with the deletion, and at least seven haplotypes carry other mutations.
The second major CF mutation is associated with pancreatic insufficiency and occurred in the same haplotype in which the ΔF508
arose. Only 31% of Spanish CF patients with no family history of the disease can be accurately diagnosed; about 50% of CF
carriers can be detected in the Spanish population. 相似文献
13.
Hans Scheffer David J. Bruinvels Gerard J. te Meerman Edwin Verlind Dirk Penninga Jeanette Dankert Leo P. Ten Kate Charles H. C. M. Buys 《Human genetics》1990,85(4):425-427
Summary We have determined the frequency of the major cystic fibrosis (CF) three base pair deletion (ΔF508) mutation in 152 CF chromosomes
from patients originating from the northern part of The Netherlands. In these patients, the deletion represents approximately
76% of CF mutations. Meconium ileus is strongly associated with homozygosity for the ΔF508 mutation. The XV2c,KM19 haplotypes
on the CF chromosomes without the ΔF508 mutation are in disequilibrium with the population frequency, although showing an
increased frequency of the 1 2 haplotype. The surplus of this haplotype is almost entirely made up by the pancreatic insufficient
patients. 相似文献
14.
The haplotype distribution of the ΔF508 mutation in cystic fibrosis families in Scotland 总被引:1,自引:0,他引:1
Iain McIntosh Ann Curtis Maria-Luz Lorenzo Marion Keston Annette J. Gilfillan Gillian Morris David J. H. Brock 《Human genetics》1990,85(4):419-420
Summary The gene defective in cystic fibrosis (CF) has recently been isolated and the major mutation identified. The haplotype distribution
of this mutation (ΔF508) has been determined for 215 CF chromosomes in the Scottish population. ΔF508 represents 73% of all
CF mutations in this group. There remains considerable linkage disequilibrium between XV2c and KM19 and other mutations in
the CF gene. 相似文献
15.
Milan Macek Jr. Vera Vavrová Ingolf Böhm Manfred Stuhrmann André Reis Ruzena Duspivová Milan Macek Karl Sperlinge Michael Krawczak Jörg Schmidtke 《Human genetics》1990,85(4):417-418
Summary This study analyses distribution patterns of the ΔF508 mutation of the cystic fibrosis transmembrane conductance regulator
gene (CFTR) gene and the cystic fibrosis (CF)-linked marker loci MET, D7S23, D7S399, and D7S8 in a sample of 167 (116 complete)
CF families from Bohemia and Moravia (Czechoslovakia). DNA typing was performed by polymerase chain reaction amplification,
restriction analysis, and agarose or polyacrylamide gel electrophoresis. The frequency of the ΔF508 mutation in this sample
is 67% and the frequency of the B haplotype is 77.6% on CF chromosomes. Linkage disequilibrium was found between ΔF508 and
all markers tested. 相似文献
16.
Marianne Schwartz Helle Krogh Johansen Christian Koch Niels Jacob Brandt 《Human genetics》1990,85(4):427-428
Summary We have investigated the frequency of the ΔF508 mutation on cystic fibrosis (CF) chromosomes in Denmark. Of 304 chromosome
tested, 86.8% have the ΔF508 mutation. The majority of the chromosomes with this mutation are found on chromosomes with the
XV2c/KM19 haplotype B (97.3%), whereas 15/16 chromosomes with haplotype C have another mutation, confirming that only very
few mutations will account for the majority of CF genes in the Danish population. 相似文献
17.
Diane E. Grove Meredith F.N. Rosser Hong Yu Ren Anjaparavanda P. Naren Douglas M. Cyr 《Molecular biology of the cell》2009,20(18):4059-4069
Premature degradation of CFTRΔF508 causes cystic fibrosis (CF). CFTRΔF508 folding defects are conditional and folding correctors are being developed as CF therapeutics. How the cellular environment impacts CFTRΔF508 folding efficiency and the identity of CFTRΔF508''s correctable folding defects is unclear. We report that inactivation of the RMA1 or CHIP ubiquitin ligase permits a pool of CFTRΔF508 to escape the endoplasmic reticulum. Combined RMA1 or CHIP inactivation and Corr-4a treatment enhanced CFTRΔF508 folding to 3–7-fold greater levels than those elicited by Corr-4a. Some, but not all, folding defects in CFTRΔF508 are correctable. CHIP and RMA1 recognize different regions of CFTR and a large pool of nascent CFTRΔF508 is ubiquitinated by RMA1 before Corr-4a action. RMA1 recognizes defects in CFTRΔF508 related to misassembly of a complex that contains MSD1, NBD1, and the R-domain. Corr-4a acts on CFTRΔF508 after MSD2 synthesis and was ineffective at rescue of ΔF508 dependent folding defects in amino-terminal regions. In contrast, misfolding caused by the rare CF-causing mutation V232D in MSD1 was highly correctable by Corr-4a. Overall, correction of folding defects recognized by RMA1 and/or global modulation of ER quality control has the potential to increase CFTRΔF508 folding and provide a therapeutic approach for CF. 相似文献
18.
M Ravnik-Glavac P Gasparini B Peterlin M Strukelj D Glavac N Canki-Klain P F Pignatti R Komel 《Annales de génétique》1992,35(2):85-88
The authors used polymerase chain reaction to analyse 56 Slovenian cystic fibrosis (CF) chromosomes for the presence of delta F508 and eight other most frequent mutations located in exons 7,11 and 20 (R347P, R334W, G551D, R553X, S549RA, S549RT, S549I and S1255X) of the CF gene. We also determined the frequency of haplotypes associated with CF for six linked RFLP markers (MetD/TaqI, MetH/TaqI, XV-2c/TaqI, KM-19/PstI, MP6d9/MspI and J3.11/MspI) in 27 Slovenian CF families. delta F508 mutation was present in 55.4 percent of the CF chromosomes. No case of the other mutations were detected in the sample of tested CF chromosomes. A very high degree of association (0.88) has been found between DNA marker MetH and CF (as measured by the Yule's association coefficient) in our population. Using the RFLP markers XV-2c and KM-19, we found that 85% of delta F508 mutated chromosomes have a single 1 2 (B) haplotype, and that this haplotype is present on only 15.4 percent of CF chromosomes without this deletion. 相似文献
19.
M. J. Schwarz M. Super C. Wallis P. Beighton C. Newton L. E. Heptinstall C. Summers A. Markham G. Hambleton K. W. Webb D. Bilto D. Heaf M. Dalzell 《Human genetics》1990,85(4):428-430
Summary Details of haplotype and ΔF508 status from various populations represented in the cystic fibrosis (CF) DNA bank of the Royal
Manchester Children's Hospital are provided, together with information on the association of genotype and clinical status.
Clinical details and DNA analyses from native English in the North-West and South-West of England (Bath), from Lancashire
Pakistani families and from Afrikaans Namibian families are compared. A 78.5% incidence of ΔF508 has been found in English
families. Compound heterozygotes with CF and only one ΔF508 gene have an increased likelihood of having milder disease, with
lessPseudomonas isolated from sputum and relatively more showing either no regular respiratory pathogens or colonisation withStaphylococcus. There is also a relative increase in meconium ileus in these compound heterozygotes. The diagnosis of CF may be in doubt
in some subjects negative for ΔF508. Some of the Bath families have unusual haplotypes for an English population and a compound
heterozygote ΔF508/ΔI507 has been found. There is evidence from metD analysis of the founder effect in the Afrikaans Namibian
families, who have a high ΔF508 incidence. 相似文献
20.
D Hillaire J C Chomel F Lesure M Renouil C Musenger F Pierson M Berthelon G Lenoir G Gérard E Bois 《Annales de génétique》1991,34(1):5-7
The frequencies of the delta F 508 mutation and haplotypes linked to the cystic fibrosis (CF) gene and detected with DNA probes XV-2C and KM-19 have been studied in the population of Reunion Island, a French province located in the Indian Ocean. The deletion was present in 41.3% of CF chromosomes, whereas this proportion is about 70% in the French population. The delta F 508 mutation was associated with the haplotype B defined by the DNA markers XV-2C (allele 1) and KM-19 (allele 2) in 76.4% of CF chromosomes, while this proportion is over 90% in the French population. Founder effect, genetic drift and admixture can explain these differences. 相似文献