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Biomedical subjects

X Estivill

Publications and source records attributed to X Estivill.

At least 325 records · Page 18Linked to original sources
PubMed1988

Isolation of a human gene with protein sequence similarity to human and murine int-1 and the Drosophila segment polarity mutant wingless.

An expressed gene sequence which was identified by the isolation of a methylation free CpG island from human chromosome 7 has been cloned from a human lung cDNA library. The deduced protein sequence contains 360 amino acids and has several features of a secreted protein; it is cysteine rich with a signal peptide sequence and two potential asn-linked glycosylation sites. The protein sequence shows marked similarity with human and murine int-1 and their Drosophila homolog wingless (Dint-1). This human int-1 related protein, int-1 and Dint-1 have diverse patterns of expression, but the inferred structural similarities suggest that some of the functional characteristics of these proteins may be shared.

Amino Acid Sequence↗
PubMed1988

Detection of a rare-cutter RFLP in a CpG-rich island near the cystic fibrosis locus.

The probe pCS.7, isolated from an HpaII tiny fragments (HTF) island and tightly linked to the mutation causing cystic fibrosis (CF), detects a polymorphism with the rare-cutter restriction enzyme BssHII. In a single digest, the resulting restriction fragment length polymorphism (RFLP) cannot be detected by either conventional or pulse-field gel electrophoresis. A double digest with BssHII in conjunction with a six-cutter restriction enzyme that does not recognize a site containing a CpG dinucleotide enables the probe to be used routinely for prenatal diagnosis and carrier exclusion. This strategy can be used to identify polymorphisms in HTF islands.

Alleles↗
PubMed1988

Linkage disequilibrium between cystic fibrosis and linked DNA polymorphisms in Italian families: a collaborative study.

The locus D7S23 includes a CpG-enriched methylation-free island that maps midway between the markers J3.11 and met and is genetically very close to the mutation causing cystic fibrosis (CF). We have studied the linkage disequilibrium between four polymorphic markers from this locus (KM.19, CS.7, XV-2c, and PT-3) and the CF mutation (CF) in 127 Italian families. Strong linkage disequilibrium is found between KM.19, CS.7, and CF, and weaker but significant disequilibrium is found between XV-2c, PT-3, and CF. The disequilibrium between markers and CF for the Italian population provides additional information on the origin and homogeneity of the CF defect. This panel of probes is sufficiently informative to permit accurate prenatal diagnosis of CF in most families with an affected person, and the disequilibrium also allows indirect carrier detection/exclusion in some cases.

Alleles↗
PubMed1988

Determination of the spectrum of beta-thalassemia genes in Spain by use of dot-blot analysis of amplified beta-globin DNA.

We have delineated the molecular lesions causing beta-thalassemia in Spain, a country that has witnessed the passage of different Mediterranean populations over the centuries, in order to evaluate the extent of heterogeneity of these mutations and to make possible simplified prenatal diagnosis of the disorder in that country. The use of the polymerase chain-reaction (PCR) technique to preferentially amplify beta-globin DNA sequences that contain the most frequent beta-thalassemia mutations in Mediterraneans enabled us to rapidly analyze 58 beta-thalassemia alleles in a dot-blot format either by hybridization with allele-specific radiolabeled oligonucleotide probes or by direct sequence analysis of the amplification product. The Spanish population carries seven different beta-thalassemia mutations; the nonsense codon 39 is predominant (64%), whereas the IVS1 position 110 mutation, the most common cause of beta-thalassemia in the eastern part of the Mediterranean basin, is underrepresented (8.5%). The IVS1 mutation at position 6 accounts for 15% of the defects and leads to a more severe form of beta+-thalassemia than originally described in most of the patients we studied. In this study, we demonstrate further the usefulness of the dot-blot hybridization of PCR-amplified genomic DNA in both rapid population surveys and prenatal diagnosis of beta-thalassemia.

Base Sequence↗
PubMed1987

Physical and genetic analysis of cosmids from the vicinity of the cystic fibrosis locus.

Cosmid libraries have been constructed from DNA of somatic cell hybrid cell lines, each containing a fragment of human chromosome seven and including sequences closely linked to cystic fibrosis (CF). Cosmids containing human DNA as insert were isolated from the library. Three cosmids, when used as probes to total genomic DNA, detected polymorphic loci, each of which was shown to be in strong linkage disequilibrium with CF. Restriction endonuclease digestion of cosmid clones and use of a new, rapid method of chromosome walking based on competitive hybridisation of cosmid inserts has allowed identification of several groups of overlapping cosmids ("contigs") from the vicinity of CF.

Animals↗
PubMed1987

A rapid method to identify cosmids containing rare restriction sites.

A procedure for identifying specific cosmid clones containing recognition sites for "rare cutting" restriction enzymes has been developed. Cosmid clones containing human inserts were selected by hybridisation to human repetitive DNA. An oligonucleotide corresponding to the NotI recognition site, eight bases long, was labelled and used to probe DNA samples from one hundred cosmids. By optimising the difference in melting characteristics between eight-base perfect match and six-base match/two base mismatch hybrids, we were able to detect the cosmids containing either NotI (8 bp match) or XmaIII/EagI (6 bp match) sites. The generation of a map for rare cutter sites along a human chromosome, or a chromosome region, should be simplified using this approach, which will enable the identification of a set of "milestones" at intervals of several hundred kilobases (kb) along the DNA sequence.

Base Sequence↗
PubMed1987

Patterns of polymorphism and linkage disequilibrium for cystic fibrosis.

Four polymorphic markers that map within 80 kb of an HTF island which is genetically very close to the cystic fibrosis locus have been identified. We have analyzed the linkage disequilibrium between each of these markers and the cystic fibrosis mutation in 89 families from four European countries, Denmark, Finland, Spain, and Great Britain. Strong linkage disequilibrium between three polymorphic sites and cystic fibrosis was observed. The markers on the J3.11 (D7S8) side of the HTF island show stronger disequilibrium than those on the met side. Linkage disequilibrium between markers and disease alters the probability that a person of a given haplotype is a carrier in some populations and helps to identify regions of a sequence that are most likely to contain the cystic fibrosis mutation.

Chromosome Mapping↗
PubMed1987

The cystic fibrosis locus.

The identification of the cystic fibrosis locus (CF) provides a model for the study of single gene defects where the biochemical lesion is not known. Using families each of which has several affected siblings, it was possible to exclude a number of 'candidate genes' which had previously been proposed as possible sites of the CF mutation. Exclusion mapping of the genome using polymorphic protein and DNA markers showed that CF is on the long arm of human chromosome 7. The most closely linked flanking markers were identified, and human chromosome fragments containing them (and therefore the CF locus) were isolated in rodent cell lines by chromosome-mediated gene transfer. The transgenome was then analysed using cosmid contig mapping, pulse-field gel electrophoresis, HTF island identification and linkage disequilibrium. In this way, a candidate coding sequence has been identified which always segregates with CF.

Animals↗
PubMed1987

Linkage of DNA probe B79a (D7S13) to cystic fibrosis.

We have conducted, in 64 affected families, a study of linkage between the anonymous DNA segment pB79a (D7S13) and the locus for cystic fibrosis (CF) on chromosome 7q. The maximum lod score was 12.60 at theta = .08 (confidence bounds .045-.135). Although D7S13 is not sufficiently close to CF for routine use in DNA-based prenatal diagnosis, it will be helpful in certain families when other nearby markers are uninformative. D7S13 will also be useful for refining the linkage map of the CF region.

Cystic Fibrosis↗
PubMed1987

The application of molecular genetics to the study of the basic defect causing cystic fibrosis.

The first linkage to CF was demonstrated to the enzyme paroxonase, a classical protein polymorphism, by the Copenhagen group. This was followed quickly by six cloned DNA sequences: pJ3.11, 7C22, COL1A2 and TCRB (St. Mary's), 917 (Toronto) and met (Salt Lake City). Both pJ3.11 and met are very close genetically to the CF mutation, and can be used for carrier detection and antenatal diagnosis in many informative families where there is a CF child. There is no evidence for heterogeneity of the CF locus. The collection of markers surrounding the CF locus is now sufficient to permit attempts to be made to isolate the defective gene using a combination of chromosome-mediated gene transfer, pulse field gel electrophoresis, NotI junction libraries, cosmid mapping and chromosome walking techniques.

Chromosome Mapping↗
PubMed1987

Rearrangement of the c-myc oncogene with heavy-chain immunoglobulin enhancer in tumor DNA from an acute lymphoblastic leukemia patient.

The DNA obtained from the leukemia cells of an acute lymphoblastic leukemia (ALL, L3 type) with a pre-B-phenotype and a typical t(8;14) chromosomal translocation showed a rearrangement juxtaposing the c-myc gene and the immunoglobulin (Ig) heavy-chain gene enhancer. This abnormality was only present in the leukemia cells of the patient and correlated with the clinical course of the disease. The breakpoint on chromosome 8 occurred within c-myc intron 1, between 790 and 638 base pairs upstream of c-myc exon 2. This breakpoint position was the nearest to the c-myc exon 2 so far described in Burkitt's type lymphoma-leukemias, and it mapped very near to the location of a major cryptic promoter used by truncated c-myc genes. In spite of what was detected in a human lymphoma cell line (Manca) carrying a similar rearrangement, in this case the amount of c-myc transcript was not increased compared to an Epstein-Barr virus-transformed normal lymphoblastoid cell line obtained from the same patient. This may in part be due to the breakpoint position and to the fact that the efficiency of the major cryptic promoter present within the first intron could have been affected by the translocation event. Finally, as previously suggested by others, the phenotype expressed by the leukemia cells supported the notion that this particular type of rearrangement (linking together the c-myc gene and the Ig heavy-chain gene enhancer element) may be associated with a subgroup of B-ALLs showing an immunologic phenotype relatively more immature than that of classical B-ALL.

Adult↗
PubMed1987

Exclusion of catalytic and regulatory subunits of cAMP-dependent protein kinase as candidate genes for the defect causing cystic fibrosis.

Cystic fibrosis (CF) is a common autosomal recessive disease with significant morbidity and mortality. Defects in cAMP control mechanisms are implicated in the pathophysiology of the disease. The mutation causing CF has been localized to chromosome 7q22-7q31.1. We have used (1) somatic-cell hybrids containing this region of the human genome in a mouse background and (2) segregation analysis in families to exclude both the genes coding for a catalytic subunit and three distinct regulatory subunits of cAMP-dependent protein kinase as candidates for the gene defect in CF. Two of these genes--those for the human homologue of the mouse type I regulatory subunit and the human homologue of the rat type II regulatory subunit--map to human chromosome 7.

Animals↗
PubMed1986

Chromosome assignment and restriction fragment length polymorphism analysis of the anonymous DNA probe B79a at 7q22 (HMG8 assignment D7S13).

The anonymous DNA fragment B79a, which had previously been located to chromosome 7cen-7q22, has been more accurately assigned to 7q22 by dosage analysis in a patient hemizygous for a deletion of that region. By examination of a panel of genomic DNAs from unrelated individuals, digested with a number of different restriction enzymes, we have identified two frequent RFLPs detected by B79a. This probe will be important in the analysis of cystic fibrosis which has been mapped to the region around 7q22.

Chromosome Mapping↗