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Biomedical subjects

X Estivill

Publications and source records attributed to X Estivill.

At least 271 records · Page 15Linked to original sources
PubMed1993

Presymptomatic analysis of spinocerebellar ataxia type 1 (SCA1) via the expansion of the SCA1 CAG-repeat in a large pedigree displaying anticipation and parental male bias.

Autosomal dominant cerebellar ataxia type 1 (ADCA1) is a clinical and genetic heterogeneous neurodegenerative disorder which leads to progressive cerebellar ataxia. One defective gene responsible for the disease was first localised to 6p (SCA1, spinocerebellar ataxia type 1) and the mutation has been more recently characterised. We have analysed the CAG-repeat mutation responsible for the SCA1 phenotype in a large Spanish kindred with 41 affected members, in which positive linkage with D6S89 was previously shown. All (10) clinically affected members analysed were heterozygous with one disease allele being between 41 to 57 CAG repeats, and the other in the normal range, from 6 to 39 repeats. Nine clinically unaffected individuals who were between the ages of 18 and 40, were found to have expansions of the CAG repeat (41 to 59), and 22 other 'at risk' individuals were found to have inherited the SCA1 gene with copies of the CAG repeat in the normal range. We have also observed that affected fathers passed on the mutated SCA1 gene with larger increases in the number of CAG repeats than affected mothers did. In one case a decrease in the number of CAG repeats (51 to 50) was detected in the transmission from the affected mother, and in two cases no change was observed in the transmission of a 41 allele repeat by a mother. As in the other disorders in which knowledge of the mutation has been obtained, analysis of the repeat expansion dramatically changes diagnosis of SCA1.

Adolescent↗
PubMed1993

Uniparental inheritance of microsatellite alleles of the cystic fibrosis gene (CFTR): identification of a 50 kilobase deletion.

More than 250 mutations have been detected in the cystic fibrosis (CF) transmembrane regulator (CFTR) gene, most of which are single point mutations or small deletions or insertions of a few nucleotides. Here we report the first large deletion identified in the CFTR gene, which involves 50 kb in two stretches of DNA: one of 10 kb from exon 4 to exon 7, and another of 40 kb, spanning exons 11 to 18. The deletion has been detected via uniparental inheritance of CFTR microsatellite alleles (IVS17BTA and IVS17BCA) in 3 independent CF families. Clinical status of the 3 CF patients, of which two have the delta F508 mutation as the other CF allele, suggests that this mutation is responsible for a severe clinical phenotype, indistinguishable from homozygous delta F508 patients. The deletion detected here suggests that other large, but less complex molecular defects could also exist in the CFTR gene.

Adult↗
PubMed1993

Novel alleles, hemizygosity and deletions at an Alu-repeat within the neurofibromatosis type 1 (NF1) gene.

Neurofibromatosis type 1 (NF1) (von Recklinghausen) is a common autosomal dominant disorder, characterised by the presence of peripheral neurofibromas, café-au-lait spots and Lisch nodules of the iris. Due to the high mutation rate at the NF1 locus, most patients are expected to have different mutations, limiting molecular analysis and genetic counseling to the identification of the mutation in each patient or family, or to the use of DNA polymorphisms. We have analysed an Alu-repeat polymorphic sequence (AAAT), located in intron 27 of the NF1 gene, in 70 NF1 and 40 CEPH families and we have detected several genetic and molecular abnormalities. In two families the NF1 individuals were hemizygous at the AAAT-repeat and/or at the CA-repeat of intron 27 of NF1, due to interstitial deletions, which include intron 27 to exon 37 of the NF1 gene. A 71-bp deletion at the Alu sequence was detected in non-NF1 chromosomes of members of three NF1 families. New alleles at the AAAT-repeat were found in one NF1 family and in three CEPH families giving a mutation rate for this AAAT-repeat of 0.36% per allele, which is one of the highest detected for a microsatellite locus.

Alleles↗
PubMed1993

Haplotype analysis to determine the position of a mutation among closely linked DNA markers.

Positional cloning involves first finding linkage between an inherited phenotype (such as a disease) and a DNA marker, followed by the use of a variety of physical and genetic mapping techniques to move from linkage to mutation. If there is a founder effect within a population, crossovers are often rare between the mutation causing the phenotype and closely situated markers and increasing disequilibrium may be observed as the site of the mutation is approached. Standard coefficients of disequilibrium may, however, be insensitive to the relative position of close markers and the mutation, because they depend upon allele frequencies in the normal population compared to those of the founder chromosome. Using cystic fibrosis in European populations as a model system, alternative methods for determining the position of a mutation are discussed. These include haplotype parsimony and three-way interval likelihood analysis. Both methods predict the location of the major CF mutation accurately from a real set of more than 600 European CF chromosomes.

Alleles↗
PubMed1993

Microsatellite haplotypes for cystic fibrosis: mutation frameworks and evolutionary tracers.

Highly informative intragenic microsatellite markers within the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene allow the analysis of associations between specific mutations and haplotypes. We have analysed 440 Spanish CF families carrying 22 different CF mutations and have established haplotypes in 1,036 chromosomes for microsatellites IVS8CA, IVS17BTA and IVS17BCA. No new alleles were detected at the three CFTR microsatellites, in more than 3,000 meiosis analysed (estimated mutation rate of less than 3.3 x 10(-4)). The evolution of 16 haplotypes associated with the most common CF mutation, delta F508, and the low mutation rate at these microsatellite loci suggest that delta F508 originated within the 23-31-13 haplotype at least 53,000 years ago, very early in the history of the European population. The number of haplotype changes seen for two other common mutations, G542X (haplotype 23-33-13) and N1303K (23-31-13), suggests that they originated at least 35,000 years ago. Microsatellite allele variability associated with delta F508, G542X and N1303K demonstrates that slippage and mispairing is the main mechanism generating microsatellite alleles. In spite of the haplotype variability detected for these 3 common mutations, the association between haplotype and mutations is very strong. Mutations 1609delCA, 3667del4, delta I507 and G551D are all associated with haplotype 16-7-17, which has a frequency of 14.5% in normal chromosomes. 5 haplotypes bearing specific CF mutations were not found in normal chromosomes. Haplotype 16-46-13 is strongly associated with CF mutations E92K and 3601-111G-->C. About 23% of CF chromosomes with unknown mutations show significant linkage disequilibrium for microsatellite haplotypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1992

[Polymorphism MI detected through the enzyme MspI in the study of congenital protein C deficiency].

BACKGROUND: In order to find alternatives for the diagnosis of hereditary protein C (PC) deficiency, we have studied the diagnostic informativity of the restriction fragment length polymorphism (RFLP) MI, located 7 kb upstream of the PC gene and detected with the restriction enzyme MspI. METHODS: The RFLP MI has been analysed in 77 individuals belonging to 27 families with congenital PC deficiency, as well as in a control group of 46 healthy donors. The analysis has been performed by PCR amplification and MspI digestion of the polymorphic DNA fragment. RESULTS: The allelic frequencies of the RFLP MI in the population studied are 0.69 for the allele A1, without the MspI restriction site, and 0.31 for the allele A2, with the MspI site. No differences have been found between the control and the PC deficient groups. The informativity of the polymorphism has been calculated to be 33.8%. Consegregation studies between this RFLP and PC deficiency have allowed the determination of the allele associated to the polymorphism in 21 out of the 27 studied families. Furthermore, an asymptomatic PC deficient carrier, with normal PC levels, has been identified. CONCLUSIONS: The study of this RFLP in families with hereditary PC deficiency may be useful for the identification of PC deficient carriers as well as for the prenatal diagnosis of the deficiency.

Alleles↗
PubMed1992

Cystic fibrosis patients with mutation 1949del84 in exon 13 of the CFTR gene have a similar clinical severity as delta F508 homozygotes.

The majority of the identified cystic fibrosis (CF) mutations are very uncommon in the total patient population, making the correlation between the clinical presentation and the molecular alterations difficult. The largest deletion that has been described so far in CF is of 84 bp in exon 13, which corresponds to the regulatory (R) domain of the CF transmembrane conductance regulator (CFTR) protein. We have analysed 340 Spanish CF patients for this deletion, named 1949del84, and found three further compound heterozygous patients for mutations 1949del84 and delta F508, and one for 1949del84 and an unknown mutation. Evaluation of the clinical data in these patients suggests that this in-frame deletion, when associated with delta F508, has a similar disease severity to that of delta F508 homozygous patients.

Adolescent↗
PubMed1992

Protein C deficiency: identification of a novel two-base pair insertion and two point mutations in exon 7 of the protein C gene in Spanish families.

We have applied single-strand conformation polymorphism (SSCP) to the analysis of exon 7 of the anticoagulant protein C (PC) gene, in 13 PC-deficient Spanish families. Abnormal patterns were visualized in three samples from type I or quantitative PC deficient proposita. A previously undescribed mutation due to a TT insertion after nucleotide 6139, between codons Gly-142 and Arg-143 was found in one family. The mutation (6139,ins TT) should result in a frameshift with a stop at codon 156, which agrees with the presence of a type I or quantitative PC deficiency in the affected members of the family. The second mutation identified was a C to T transition at nucleotide 6274, 9 base pairs into intron G. This mutation (6274,C-->T), found for the first time in a Spanish family, is identical to the previously characterized PC Sant Louis. The third mutation was a G to A transition that replaces arginine 178 with glutamine (178,R-->Q). This is the third case of 178,R-->Q mutation in 17 apparently unrelated Spanish families with type I PC deficiency. Furthermore, SSCP analysis allowed the detection of another previously described mutation in a PC-deficient Spanish family (178,R-->W).

Base Sequence↗
PubMed1992

Multiplex PCR amplification of three microsatellites within the CFTR gene.

Multiplex PCR amplification has been developed for three highly polymorphic microsatellites (IVS8CA, IVS17BTA, and IVS17BCA) located in intronic regions of the CFTR (cystic fibrosis (CF) transmembrane conductance regulator) gene. The triplex PCR reaction required different concentrations of each pair of primers and labeling of primers in the same reaction. Total informativity is obtained in 90.25% of couples requiring analysis of polymorphisms, and when triplex microsatellite analysis is combined with analysis for the six most common CF mutations in the Spanish population, informativity reaches more than 99%.

Base Sequence↗