Linkage relationships and allelic associations of the cystic fibrosis locus and four marker loci

Schmidtke, Jörg; Krawczak, Michael; Schwartz, Marianne; Alkan, M.; Bonduelle, Mary-Louise; Bühler, Erica M.; Chemke, M.; Darnedde, T.; Domagk, J.; Engel, Wolfgang; Frey, Daniel; Fryburg, K.; Halley, D. J. J.; Hundrieser, J.; Ladanyi, L.; Libaers, I.; Lissens, Willy; Mächler, M.; Malik, Naseem; Morreau, J.; Neubauer, V.; Oostra, Ben A.; Pape, B.; Poncin, Jacques; Schinzel, Albert; Simon, Patricia; Trefz, Friedrich K.; Tümmler, Burkhard; Vassart, Gilbert; Voss, R.

doi:10.1007/bf00272441

Cited by 28 publications

(10 citation statements)

References 9 publications

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“…In addition, allele frequencies on N chromosomes for the RFLPs 3.11 (MspI), and met H (MspI, TaqI) and met D (TaqI) did not differ significantly from data in the literature. However, the difference of allele frequencies between N and CF chromosomes for the three more distant marker loci, particularly for MET H was less pronounced in our families than reported from the collaborative North American (Beaudet et al 1986) and European studies (Schmidtke et al 1987) and from the other German groups (Weber et al 1988) (Tables 2, 3). This study a Compiled German data (Mathy et al 1987;Schmidtke et al 1987;Krawczak et al 1988;Weber et al 1988) Compiled European data (Estivill et al 1987a, b;Schmidtke et al 1987) Compiled North American data (Beaudet et al 1986(Beaudet et al , 1989 a Data from the two crossover families (N, CF) and from the seven families with incomplete parental haplotypes were excluded majority of adult patients was either 1-2 in MET D (group VI), or 1-1 in D7S8 and MET D and 1-2 in MET H (group II).…”

Section: Allelic Associationcontrasting

confidence: 70%

Marker haplotype association with growth in German cystic fibrosis patients

et al. 1990

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In 84 families with 101 children with cystic fibrosis (CF) and 103 unaffected siblings, the haplotype of CF chromosomes was determined with six restriction fragment length polymorphism (RFLP) markers that span the CF gene locus. Patient groups with different genotypes in the more distant flanking marker loci MET D, MET H, and D7S8 differed significantly from each other with respect to percentile height and weight, and percentage of weight for height. Patients homozygous 1-1 in met D (TaqI) and met H (TaqI) were thin and tall when homozygous 1-1 in J3.11 (MspI), and small when homozygous 2-2 in J3.11. Heterozygosity in 3.11 and met H and homozygosity 1-1 in met D segregated with the most severe growth retardation. In contrast, growth was normal in patients who were heterozygous in met D and/or had an uncommon KM.19/XV-2c haplotype. Most patients with pancreatic sufficiency and/or borderline sweat test values were carrying rare haplotypes on their CF chromosomes. Adult patients clustered in genotype groups with normal height percentile distributions. This association between haplotype and clinical severity of CF in the German population provides evidence for genetic microheterogeneity of the CF locus, either because of the existence of multiple alleles of the CF gene itself and/or because of the existence of closely linked polymorphic genes that control growth and development and hence modulate the clinical course and prognosis of CF.

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Section: Allelic Associationcontrasting

confidence: 70%

Marker haplotype association with growth in German cystic fibrosis patients

et al. 1990

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“…Successive collaborative linkage analyses of various molecular markers (Beaudet et al 1986; Bartels et al 1986;Farall et al 1986;White et al 1986;Schmidtke et al 1987;Lathrop et al 1988;Farall et al 1988) have resulted in the physical-genetical map presented in Fig. 1 (from Farall et al 1988, andRiordan et al 1989).…”

Section: Introductionmentioning

confidence: 99%

Studies of RFLP closely linked to the cystic fibrosis locus throughout Europe lead to new considerations in populations genetics

Serre¹,

Simon‐Bouy²,

Mornet³

et al. 1990

Hum Genet

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The prenatal diagnosis of cystic fibrosis is now routinely performed by using two probes tightly linked to the CF locus (XV2C and KM19). These probes have been shown to exhibit a strong linkage disequilibrium with the CF locus. Our data (103 families) have been pooled with other French data (237 families). They are consistent with the hypothesis of a unique ancestral mutation initially associated with a B (D1E2) restriction fragment length polymorphism (RFLP) haplotype, subsequently reassociated by cross-over with A, C or D haplotypes. Assuming such an hypothesis, the mutation is supposed to be 3000-6000 years old, depending on generation length and the true recombination ratio between the KM19 and CF loci. Up-to-date Spanish, Danish and Greek data are reported together with other previously published population data in order to discuss the geographic origin and age of the mutation in Europe. The action of selection in terms of heterozygote advantage and distorsion of segregation is discussed.

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“…The GATT-polymorphism (allele 1:7 repeat, allele 2:6 repeat) was detected by the difference in mobility of the PCR product on 10% polyacrylamide gels. Haplotypes for the polymorphisms metH (TaqI) and metD (TaqI) were ascertained by Southern blot analysis with radioactive probes (Schmidtke et al 1987).…”

Section: Haplotype Analysismentioning

confidence: 99%

Cystic fibrosis with three mutations in the cystic fibrosis transmembrane conductance regulator gene

Dörk¹,

Wulbrand²,

Richter³

et al. 1991

Hum Genet

104

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Three mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene were discovered in a pancreas-insufficient patient with cystic fibrosis (CF) who displayed an uncommon combination of almost normal chloride concentration in sweat tests and typical symptoms of gastrointestinal and pulmonary disease. The R553Q mutation was found on the maternal delta F508-CFTR gene. Codon 553 is located within a consensus motif of the ATP-binding cassette transport proteins at a less conserved position. Other members of this protein superfamily contain a glutamine instead of arginine at the homologous position, suggesting a modulating rather than disease-causing role of the R553Q mutation in CFTR. The amplification refractory mutation system did not detect the R553Q mutation in a further 65 normal, 113 delta F508, and 91 non-delta F508 CF chromosomes. The index case carried the R553X nonsense mutation on the paternal chromosome. The R553X mutation was present on a further 9 out of 86 German non-delta F508 CF chromosomes linked with the XV2c-KM19-Mp6d9-J44-GATT haplotypes 2-2-2-1-1 and 1-1-2-1-2. The location of R553X on separate haplotypes including both alleles of the intragenic GATT repeat suggests an ancient and/or multiple origins of the R553X mutations. The association of the genotype of the CFTR mutation and the clinical phenotype was assessed for the patients carrying the related genotypes delta F508/delta F508 (n = 80), delta F508/R553X (n = 9) and delta F508-R553Q/R553X (n = 1). In compound heterozygotes, the median chloride concentration in pilocarpine iontophoresis sweat tests was significantly lower than in the delta F508 homozygotes (P less than 0.01). The patient groups were significantly different with respect to the distributions of the centiles for height (P less than 0.001) and weight (P less than 0.01) as the most sensitive predictors of the course and prognosis in CF. Growth retardation was more pronounced in the compound heterozygotes.

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Linkage relationships and allelic associations of the cystic fibrosis locus and four marker loci

Cited by 28 publications

References 9 publications

Marker haplotype association with growth in German cystic fibrosis patients

Marker haplotype association with growth in German cystic fibrosis patients

Studies of RFLP closely linked to the cystic fibrosis locus throughout Europe lead to new considerations in populations genetics

Cystic fibrosis with three mutations in the cystic fibrosis transmembrane conductance regulator gene

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