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1.
Joachim Hundrieser Silvia Bremer Frank Peinemann Manfred Stuhrmann Nicola Hoffknecht Brigitte Wulf Jörg Schmidtke Jochen Reiss Günter Maaß Burkhard Tümmler 《Human genetics》1990,85(4):409-410
Summary The F508 deletion in the cystic fibrosis transmembrane conductance regulator (CFTR) gene was found in 8 out of 30 Turkish
cystic fibrosis (CF) chromosomes (27%). Five Turkish ΔF508 CF chromosomes were associated with the risk haplotype B in KM19
(2 allele)/XV2c (1 allele). In the Turkish population, cystic fibrosis is predominantly caused by mutations other than the
F508 deletion. 相似文献
2.
Maria Tzetis E. Kanavakis Thalia Antoniadi Stavros Doudounakis George Adam Christos Kattamis 《Human genetics》1996,99(1):121-125
To completely characterize the spectrum of mutations in the cystic fibrosis transmembrane conductance regulator gene in Greek
cystic fibrosis (CF) patients, we screened 500 CF chromosomes by denaturing gradient gel electrophoresis followed by direct
sequencing. We identified 48 mutations, accounting for 85.6% of CF chromosomes. They included eight novel mutations, three
of which we have described before and five (E822X, Y247X, 2752–26A→G, 3152delT, and 2751+T→A), which are described in this
report. The detection of such a high proportion of Greek CF mutations is important for improving prenatal and genetic diagnosis
of CF in Greece.
Received: 10 May 1996 相似文献
3.
J. K. Bayleran Hailing Yan Catherine A. Hopper Elizabeth M. Simpson 《Human genetics》1996,98(2):207-209
Cystic fibrosis (CF) is one of the most common severe autosomal recessive disorders in Caucasian populations. A mutation
in the cystic fibrosis transmembrane conductance regulator (CFTR) gene causes this disorder. Reported here is the first analysis
of CF mutations in the Maine population. We have screened 263 CF chromosomes for 16 previously reported mutations. Analysis
of DNA from 124 apparently unrelated CF patients and 15 obligate carrier parents (whose partner and affected child were unavailable
for study) resulted in the identification of 91% of the CF alleles and complete genotyping of 85% of the patients. The frequencies
(%) of these mutations in the Maine population are ΔF508 (75% of the chromosomes), G85E (0.76), R117H (0.76), I148T (1.1),
621+1G→T (1.1), 711+1G→T (3.0), A455E (1.1), 1717-1G→A (1.1), G542X (1.9), G551D (1.9), R560T (0.76), Y1092X (0.38), W1282X
(0.38), and N1303K (1.5). The exon 10 mutation, ΔI507, and the exon 11 mutation, R553X, were not observed. Surprisingly, whereas
only 5% of the alleles remain unidentified in the non-French population, the unidentified proportion in the French population
is 19%. CF testing for the Maine population will be further improved as the as yet unidentified CF mutations in this population
are characterized.
Received: 17 January 1996 / Revised: 28 February 1996 相似文献
4.
M. De Braekeleer André Chaventré Giorgio Bertorelle Claudine Verlingue Odile Raguénès Bernard Mercier Claude Férec 《Human genetics》1996,98(2):223-227
Microsatellite haplotypes were determined for 117 chromosomes carrying the four most frequent mutations in the cystic fibrosis
(CF) gene identified in the Breton population of Celtic origin, as well as for 83 normal chromosomes (noncarriers of a CF
mutation). Each of the three non-ΔF508 mutations was associated with a single haplotype: 1078delT with 16-31-13, G551D with
16-7-17, and W846X with 16-32-13. Although these results suggest identity-by-descent for each mutation, recurrent mutations,
although unlikely, could not be completely ruled out. The four most frequent haplotypes on normal chromosomes and the three
most frequent haplotypes on ΔF508 chromosomes are the same as those found in Ireland, Spain, and Italy. This suggests that
some haplotypes, associated or not with the ΔF508 mutation, were present in an ancestral population from which all four populations
descended.
Received: 27 November 1995 / Revised: 1 February 1996 相似文献
5.
M. Claustres Marie Desgeorges Philippe Moine Núria Morral Xavier Estivill 《Human genetics》1996,98(3):336-344
In order to contribute to a better understanding of the dispersion of cystic fibrosis (CF) mutations in the South of France,
seven diallelic and three multiallelic markers [three upstream of the cystic fibrosis transmembrane conductance regulator
(CFTR) gene (XV-2c, KM.19 and J44) and seven intragenic polymorphisms (IVS6A, IVS8CA, M470V, T854T, IVS17BTA, IVS17BCA and TUB18)]
were analyzed for 143 ΔF508 chromosomes, 100 CF chromosomes carrying 85 non-ΔF508 and 15 unknown mutations, and 198 normal
CFTR alleles. The study provides haplotypic data for 39 different CF mutations, which should be useful in diagnosis by haplotypic
analysis and detection of the associated mutations. A major haplotype [2-1-2-7-16-2-1-(30/31)-13-1] was found in normal chromosomes,
which should be the most ancient in the Caucasoid population. The most frequent haplotypes in normal chromosomes were associated
with 16 different non-ΔF508 mutations, suggesting that there was no preferential haplotype on which these mutations arose.
Several mutations were each associated with more than one haplotype, as the result of slippage at one or two of the three
microsatellites (ΔF508, G542X, N1303K, G85E, E585X, K710X and 2184delA) or recombination (1717-1G→A, R334W, L206W, R1162X
and Y122X). Haplotypes for the most common CFTR mutations (ΔF508, G542X, N1303K) revealed that a large number of alleles were generated by slippage at the microsatellite
loci, suggesting that they are the most ancient CF mutations. Other mutations were associated with haplotypes that were different
either at several diallelic sites (R334W) or at both diallelic and microsatellite markers (R1162X and R1158X), which is more
suggestive of recurrence. Twenty recombinations were detected among the CF mutant alleles analyzed, 75% of them occurring
in the second half of the CFTR gene. The higher mutational heterogeneity and the haplotypic variability reported in this small population from the Mediterranean
area are consistent with an earlier appearance of CFTR mutations in southern Europe than in central and northern Europe, and an earlier origin and expansion of this population.
Received: 19 February 1996 / Revised: 10 April 1996 相似文献
6.
Data from 2,666 patients with cystic fibrosis (CF) born in France, submitted during the period of 1992-1996 to the French registry for CF, were used to describe the different mutations, their frequency and their regional distribution. A total of 5,332 CF chromosomes have been analyzed, demonstrating 229 different mutations and accounting for 87% of CF genes in the French population. DeltaF508 is the most common mutation at 67.9% of CF mutations, followed by G542X (2.5%), N1303K (2.0%), 1717-1G-->A (1.2%), R553X (0.8%) and G551D (0.7%). The data show a clear geographical variation in the distribution of many of the mutations. Given the geographical heterogeneity of these mutations, carrier screening does not appear to be feasible in most French regions. 相似文献
7.
Teresa Casals Maria D. Ramos Javier Giménez Sara Larriba Virginia Nunes X. Estivill 《Human genetics》1997,101(3):365-370
We have analyzed 640 Spanish cystic fibrosis (CF) families for mutations in the CFTR gene by direct mutation analysis, microsatellite haplotypes, denaturing gradient gel electrophoresis, single-strand conformation
analysis and direct sequencing. Seventy-five mutations account for 90.2% of CF chromosomes. Among these we have detected seven
novel CFTR mutations, including four missense (G85V, T582R, R851L and F1074L), two nonsense (E692X and Q1281X) and one splice site mutation
(711+3A→T). Three variants, two in intronic regions (406-112A/T and 3850-129T/C) and one in the coding region (741C/T) were
also identified. Mutations G85V, T582R, R851L, E692X and Q1281X are severe, with lung and pancreatic involvement; 711+3A→T
could be responsible for a pancreatic sufficiency/insufficiency variable phenotype; and F1074L was associated with a mild
phenotype. These data demonstrate the highest molecular heterogeneity reported so far in CF, indicating that a wide mutation
screening is necessary to characterize 90% of the Spanish CF alleles.
Received: 3 July 1997 / Accepted: 20 August 1997 相似文献
8.
Marie Desgeorges André Mégarbané Caroline Guittard Soukeyna Carles Jacques Loiselet Jacques Demaille M. Claustres 《Human genetics》1997,100(2):279-283
Cystic fibrosis (CF) is thought to be rare among the Arab populations from the Middle East and little data have been reported
so far. We have studied a sample of 20 families living in Lebanon for several generations and who have at least one child
with CF. These families are mainly from the Maronite, Greek Catholic, Greek Orthodox, Shiite or Sunnite groups. We found a
50% rate of consanguineous marriage, independent of the community of origin. The distribution of CF genotypes was determined
through the screening of all exons of the CFTR (cystic fibrosis transmembrane conductance regulator) gene by the technique
of denaturing gradient gel electrophoresis combined with asymmetric amplification DNA sequencing. A total of ten different
mutations accounting for 87.5% of 32 unrelated CF alleles was identified, including two novel putative mutations (E672del
and IVS21-28G→A). Three mutations, ΔF508 (37.5%), W1282X (15.6%), and N1303K (9.4%) accounted for 62.5% of CF alleles. Interestingly,
in the Maronite group, 66.7% of the ΔF508 chromosomes were found to be associated with allele 7 of the IVS8(T)tract, contrasting
with the absolute linkage disequilibrium between European ΔF508 chromosomes and allele 9. During this study, two previously
undescribed polymorphisms (IVS14a + 17del5 and 2691T/C) were also identified.
Received: 2 January 1997 / Accepted: 16 March 1997 相似文献
9.
B. Tümmler T. Storrs V. Dziadek T. Dörk B. Tümmler H. von der Hardt T. Meitinger A. Golla R. M. Bertele-Harms H. K. Harms E. Schröder A. Claaß J. Rutjes R. Scheppenheim I. Bauer K. Breuel M. Stuhrmann J. Schmidke M. Linder A. Eigel J. Horst R. Kaiser M. J. Lentze K. Schmidt X. Estivill 《Human genetics》1996,97(6):727-731
The geographic distribution and origin of CFTR mutations in Germany was evaluated in 658 three-generation families with cystic
fibrosis (CF). Fifty different mutations were detected on 1305 parental CF chromosomes from 22 European countries and overseas.
The major mutation ΔF508 was identified on 71.5% of all CF chromosomes, followed by R553X (1.8%), N1303K (1.3%), G542X (1.1%),
G551D (0.8%) and R347P (0.8%). According to the grandparents’ birthplace, 74% of CF chromosomes had their origin in Germany;
the ΔF508 percentage was 77%, 75%, 70% and 62% in northern, southern, western and eastern Germany, respectively. Ten or more
mutant alleles in the investigated CF gene pool originated from Austria, the Czech Republic, Poland, Russia, Turkey and the
Ukraine. This widespread geographic origin of CFTR mutations in today’s Germany reflects the many demographic changes and
migrations in Central Europe during the 20th century.
Received: 10 October 1995 / Revised: 9 January 1995 相似文献
10.
Bienvenu T Viel M Leroy C Cartault F Lesure JF Renouil M 《Human biology; an international record of research》2005,77(5):705-714
The large heterogeneity in the cystic fibrosis (CF) gene is the main difficulty for genotype characterization. Numerous studies have reported considerable variations in frequencies of CF transmembrane conductance regulator (CFTR) mutations in different populations, such as African, Asian, or European populations. To completely characterize the spectrum of mutations in the CFTR gene in the Réunion Island population, we screened 228 CF chromosomes using denaturing high-pressure liquid chromatography and denaturing gradient gel electrophoresis following by direct sequencing. We identified 27 mutations, accounting for 93% of CF chromosomes. They included three novel mutations (M1T, 3121-3C-->G, and L1324P), which are described in this paper. The detection of such a high proportion of Réunion Island CFTR mutations is important for improving neonatal screening of CF on Réunion Island. 相似文献
11.
Miguel Chillón Teresa Casals Javier Giménez M. Dolores Ramos Ana Palacio Nuria Morral Xavier Estivill Virginia Nunes 《Human genetics》1994,93(4):447-451
We have analysed 972 unrelated Spanish cystic fibrosis patients for 70 known mutations. Analysis was performed on exons 1, 2, 3, 4, 5, 6a, 6b, 7, 10, 11, 12, 13, 14a, 14b, 15, 16, 17b, 18, 19, 20 and 21 of the cystic fibrosis transmembrane regulator gene using single strand conformation polymorphism analysis and denaturing gradient gel electrophoresis. The major mutation F508 accounts for 50.6% of CF chromosomes, whereas another 42 mutations account for 27.6% of CF chromosomes, with 21.8% of Spanish CF chromosomes remaining uncharacterised. At present, we have identified 36 mutations that have frequency of less than 1% and that are spread over 15 different exons. This indicates that, in the Spanish population, with the exception of F508 (50.6%) and G542X (8%), the mutations are not concentrated in a few exons of the gene nor are there any predominating mutations. This high degree of genetic heterogeneity is mainly a result of the different ethnic groups that have populated Spain and of the maintenance of separated population sets (Basques, Arab-Andalusian, Mediterranean, Canarian and Gallician). The high proportion of CF chromosomes still unidentified (21.8%) together with association analysis with intragenic markers suggest that at least 100 different mutations causing CF are present in our population. 相似文献
12.
Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease 总被引:14,自引:6,他引:8 下载免费PDF全文
Tzipora Shoshani Arie Augarten Ephraim Gazit Nurit Bashan Yaakov Yahav Yosef Rivlin Asher Tal Hagit Seret Liora Yaar Eitan Kerem Bat-sheva Kerem 《American journal of human genetics》1992,50(1):222-228
Only about 30% of the cystic fibrosis chromosomes in the Israeli cystic fibrosis patient populations carry the major CF mutation (delta F508). Since different Jewish ethnic groups tended to live as closed isolates until recent times, high frequencies of specific mutations are expected among the remainder cystic fibrosis chromosomes of these ethnic groups. Genetic factors appear to influence the severity of the disease. It is therefore expected that different mutations will be associated with either severe or mild phenotype. Direct genomic sequencing of exons included in the two nucleotide-binding folds of the putative CFTR protein was performed on 119 Israeli cystic fibrosis patients from 97 families. One sequence alteration which is expected to create a termination at residue 1282 (W1282X) was found in 63 chromosomes. Of 95 chromosomes, 57 (60%) are of Ashkenazi origin. Together with the delta F508 (23% in this group), G542X, N1303K, and 1717-1G----A mutations, the identification of 92% of cystic fibrosis chromosomes of Ashkenazi origin becomes possible. Patients homozygous for the W1282X mutation (n = 16) and patients heterozygous for the delta F508 and W1282X mutations (n = 22) had similarly severe disease, reflected by pancreatic insufficiency, high incidence of meconium ileus (37% and 27%, respectively), early age at diagnosis, poor nutritional status, and variable pulmonary function. In conclusion, the W1282X mutation is the most common cystic fibrosis mutation in the Ashkenazi Jewish patient population in Israel. This nonsense mutation is associated with presentation of severe disease. 相似文献
13.
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
14.
Venegas PB Novak JM Oscar CA Sánchez FL Gutiérrez IG Rivera JM Salas JP Montero JF Grody WW 《Human biology; an international record of research》2003,75(2):179-188
Using polymerase chain reaction amplification of DNA in dried blood spots and a nonisotopic reverse dot blot hybridization method, we performed molecular genetic analysis for 6 and for 16 of the most common mutations of the cystic fibrosis transmembrane conductance regulator gene (CFTR) in 24 unrelated Costa Rican individuals with cystic fibrosis (CF). While many countries and ethnic groups have been surveyed for CF mutations since the cloning of CFTR, Costa Rica has not heretofore been studied. Moreover, Costa Rica represents an especially intriguing population because of its mixed European-African-Amerindian origins and the existence of a detailed historical record of the founding Spanish families. Thus, such a study may reveal not only the population frequencies of various mutant alleles in this country, but also something about their geographic migrations and ethnic founder effects. The most common CF mutation in Caucasians, deltaF508, was found in only 11 (23%) of the CF chromosomes studied, while the G542X mutation, relatively rare in the general population but more common in southern Europe, was observed in 12 (25%). None of the other mutations tested was found in any of the subjects. We failed to detect the second mutant allele in 17 subjects and could not detect either allele in 4 subjects. The high prevalence of the G542X mutation in our cohort, which exceeds that of both the general Caucasian population and the American Hispanic population, reflects the strong genetic influence of the original Spanish founding families of Costa Rica. These results highlight important differences in Costa Rican CF genotypes as compared both to other North American and European populations and to American Hispanics, raising important implications about isolated founder effects and strategies for population screening in that country. 相似文献
15.
Dora Angelicheva Francesc Calafell Alexey Savov Albena Jordanova Annie Kufardjieva Vania Nedkova Tanya Ivanova Petya Yankova Dimitrina Konstantinova Evgeny Genev Luba Kalaydjieva J. Galeva 《Human genetics》1997,99(4):513-520
We present data on the population genetics of cystic fibrosis (CF) in Bulgaria, obtained by comprehensive mutation analysis
and the construction of intragenic microsatellite haplotypes. The sample of 262 CF alleles analysed is representative of the
patients diagnosed during the period of referral and of the three main ethnic groups in the country. ΔF508 accounted for 100%
of Gypsy CF alleles, which thus differed significantly from both Bulgarians and ethnic Turks. In Bulgarian and Turkish CF
patients, 92% of the mutant alleles were identified, yielding a total of 25 different mutations, of which only 7 occurred
at frequencies higher than 1%. The findings were compared to other European populations and to the distribution of phenylketonuria
mutations. Genetic distances and population trees demonstrated that in the south-eastern tip of Europe, the overall distribution
of CF mutations and polymorphic haplotypes is very close to that of Mediterranean populations, with a high frequency of N1303K
and G542X, a large number of rare mutations and a prevalence of the 23 31 13 haplotype in association with ΔF508. These findings
are consistent with a main role for the Neolithic expansion in the shaping of the CF mutation spectrum in Bulgaria and southern
Europe.
Received: 1 September 1996 相似文献
16.
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
17.
Lakeman P Gille JJ Dankert-Roelse JE Heijerman HG Munck A Iron A Grasemann H Schuster A Cornel MC Ten Kate LP 《Genetic testing》2008,12(1):25-35
AIMS: To obtain more insight into the variability of the CFTR mutations found in immigrant cystic fibrosis (CF) patients who are living in Europe now, and to estimate the test sensitivity of different frequently used methods of DNA analysis to detect CF carriers or patients among these Turkish or North African immigrants. METHODS: A survey among 373 European CF centers asking which CFTR mutations had been found in Turkish and North African CF patients. RESULTS: 31 and 26 different mutations were reported in Turkish and North African patients, identifying 64.2% (113/176) and 87.4% (118/135) alleles, respectively (p < 0.001). The mean sensitivity (detection rate) of three most common CFTR mutation panels to detect these mutations differed between Turkish and North African people, 44.9% (79/176) versus 69.6% (94/135) (p < 0.001), and can be increased to 57.4% (101/176) and 79.3% (107/135) (p < 0.001), respectively, by expanding these panels with 13 mutations which have been found on two or more alleles. CONCLUSION: 35.8% and 12.6%, respectively, of CF alleles in Turkish and North African patients living in Europe now had not been identified. Among these populations, the test sensitivity of common CFTR mutation panels is insufficient for use in screening programs in Europe, even after expansion with frequent Turkish and North African mutations. This raises questions about whether and how to implement CF carrier and neonatal screening in a multiethnic society. 相似文献
18.
The spectrum of cystic fibrosis (CF) mutations in the North African population remains poorly known. In order to offer an effective diagnostic service and to determine accurate risk estimates, we decided to identify the CF mutations in 10 Algerian CF families. We carried out a chemical-clamp denaturing gradient gel electrophoresis analysis of the CFTR gene and automated direct DNA sequencing. We identified 5 mutations and we characterized 60% of the CF chromosomes. Taking advantage of the homogeneity of the sample, we report clinical features of homozygous CF patients. 相似文献
19.
T. Dörk Bernd Dworniczak Christa Aulehla-Scholz Dagmar Wieczorek Ingolf Böhm Antonia Mayerova Hans H. Seydewitz Eberhard Nieschlag Dieter Meschede Jürgen Horst Hans-Jürgen Pander Herbert Sperling Felix Ratjen Eberhard Passarge Jörg Schmidtke Manfred Stuhrmann 《Human genetics》1997,100(3-4):365-377
Congenital absence of the vas deferens (CAVD) is a frequent cause for obstructive azoospermia and accounts for 1%–2% of male
infertility. A high incidence of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has recently
been reported in males with CAVD. We have investigated a cohort of 106 German patients with congenital bilateral or unilateral
absence of the vas deferens for mutations in the coding region, flanking intron regions and promotor sequences of the CFTR
gene. Of the CAVD patients, 75% carried CFTR mutations or disease-associated CFTR variants, such as the “5T” allele, on both
chromosomes. The distribution of mutation genotypes clearly differed from that observed in cystic fibrosis. None of the CAVD
patients was homozygous for ΔF508 and none was compound heterozygous for ΔF508 and a nonsense or frameshift mutation. Instead,
homozygosity was found for a few mild missense or splicing mutations, and the majority of CAVD mutations were missense substitutions.
Twenty-one German CAVD patients were compound heterozygous for ΔF508 and R117H, which was the most frequent CAVD genotype
in our study group. Haplotype analysis indicated a common origin for R117H in our population, whereas another frequent CAVD
mutation, viz. the “5T allele” was a recurrent mutation on different intragenic haplotypes and multiple ethnic backgrounds.
We identified a total of 46 different mutations and variants, of which 15 mutations have not previously been reported. Thirteen
novel missense mutations and one unique amino-acid insertion may be confined to the CAVD phenotype. A few splice or missense
variants, such as F508C or 1716 G→A, are proposed here as possible candidate CAVD mutations with an apparently reduced penetrance.
Clinical examination of patients with CFTR mutations on both chromosomes revealed elevated sweat chloride concentrations and
discrete symptoms of respiratory disease in a subset of patients. Thus, our collaborative study shows that CAVD without renal
malformation is a primary genital form of cystic fibrosis in the vast majority of German patients and links the particular
expression of clinical symptoms in CAVD with a distinct subset of CFTR mutation genotypes.
Received: 15 April 1997 / Accepted: 29 April 1997 相似文献
20.
B. Simon-Bouy E. Mornet J. L. Serre A. Tailandier J. Boué A. Boué 《Human genetics》1990,85(4):431-432
Summary French families (n = 129) with at least one cystic fibrosis (CF) affected child and 44 unrelated subjects from the general population were tested
for the presence of the ΔF508 mutation by the polymerase chain reaction. The ΔF508/CF mutation ratio (CF: uncharacterised
CF mutations) was tested in the CF families with and without meconium ileus. The association between ΔF508 and CF mutations
and restriction fragment length polymorphism haplotypes (XV2c and KM19) has been estimated; these data suggest that the CF
chromosomes include a panel of independent and probably different mutations. 相似文献