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Biomedical subjects

Angel Carracedo

Publications and source records attributed to Angel Carracedo.

69 records · Page 4Linked to original sources
PubMed2003

Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects.

We screened index cases from 410 Spanish breast/ovarian cancer families and 214 patients (19 of them males) with breast cancer for germ-line mutations in the BRCA1 and BRCA2 genes, using SSCP, PTT, CSGE, DGGE, and direct sequencing. We identified 60 mutations in BRCA1 and 53 in BRCA2. Of the 53 distinct mutations observed, 11 are novel and 12 have been reported only in Spanish families (41.5%). The prevalence of mutations in this set of families was 26.3%, but the percentage was higher in the families with breast and ovarian cancer (52.1%). The lowest proportion of mutations was found in the site-specific female breast cancer families (15.4%). Of the families with male breast cancer cases, 59.1% presented mutations in the BRCA2 gene. We found a higher frequency of ovarian cancer associated with mutations localized in the 5' end of the BRCA1 gene, but there was no association between the prevalence of this type of cancer and mutations situated in the ovarian cancer cluster region (OCCR) region of exon 11 of the BRCA2 gene. The mutations 187_188delAG, 330A>G, 5236G>A, 5242C>A, and 589_590del (numbered after GenBank U14680) account for 46.6% of BRCA1 detected mutations whereas 3036_3039del, 6857_6858del, 9254_9258del, and 9538_9539del (numbered after GenBank U43746) account for 56.6% of the BRCA2 mutations. The BRCA1 330A>G has a Galician origin (northwest Spain), and BRCA2 6857_6858del and 9254_9258del probably originated in Catalonia (northeast Spain). Knowledge of the spectrum of mutations and their geographical distribution in Spain will allow a more effective detection strategy in countries with large Spanish populations.

Base Sequence↗
PubMed2003

Over-representation of two specific haplotypes among chromosomes harbouring BRCA1 mutations.

The BRCA1 gene is included in a 200-400 kb region that is subjected to a recombination suppression mechanism; this region shows nearly complete linkage disequilibrium for a series of common biallelic polymorphisms, all of them with rarer allele frequency close to 0.4. These series of SNPs define two major haplotypes designated as class I and class II. In the present study, we have determined haplotype classes in the index case of 106 breast/ovarian cancer families previously screened for mutations in the BRCA genes and we have found that haplotype II (the less frequent in the control population) is over-represented among chromosomes harbouring mutations in BRCA1. In addition, we have defined a subtype of chromosomes characterized by haplotype I and one specific allele for the microsatellite marker D17S855, which are also more frequently associated with BRCA1 mutations. These findings may have important consequences for the selection of families with higher probabilities of carrying mutations in the BRCA1 gene.

Gene Frequency↗
PubMed2003

A novel loss-of-function mutation (N48K) in the PTEN gene in a Spanish patient with Cowden disease.

Cowden disease, also known as multiple hamartoma syndrome, is a rare disease inherited in an autosomal dominant pattern, which confers a high risk of developing breast and thyroid carcinomas. Mutations in PTEN, a tumor suppressor gene located on chromosome 10q23, have been identified in patients with Cowden disease. In this work, the direct sequencing of all coding regions of the PTEN gene led us to the identification of N48K, a new germline PTEN missense mutation, in a patient suffering from Cowden disease. The genetic analysis of 200 chromosomes from healthy individuals revealed that the variant was not common in our population. Moreover, by functional analysis we found that the ability of PTEN N48K mutant protein to inhibit the activation of the proto-oncogene PKB/Akt was impaired, supporting the involvement of N48K mutation in Cowden disease. Loss of heterozygosity using three microsatellites (D10S215, D10S541, and D10S564) and the complete sequence analysis of PTEN exons in breast and endometrial tumor samples from the same patient were also carried out in an attempt to identify additional PTEN somatic mutations. The lack of loss of heterozygosity or additional mutations in tumor samples suggests that abnormalities of the regulatory regions of the PTEN gene or haplo-insufficiency might occur in tumors from Cowden disease patients.

Adult↗
PubMed2003

Lack of association of ankylosing spondylitis with the most common NOD2 susceptibility alleles to Crohn's disease.

OBJECTIVE: To investigate whether the 3 most common mutations in the NOD2 gene that confer susceptibility to Crohn's disease (CD) are also associated with ankylosing spondylitis (AS). METHODS: DNA from 112 patients with AS and 168 controls of homogenous Spanish ancestry were studied. The frequencies of the pathogenic alleles of NOD2 (3020insC, 2722G>C, and 2104C>T) were determined by analysis of the melting curves after hybridization with FRET probes on a Light Cycler real-time polymerase chain reaction (PCR) system. Results. NOD2 allelic frequencies in controls (3020insC, 0.009; 2722G>C, 0.009; 2104C>T, 0.042) did not significantly differ from patients with AS (3020insC, 0.009; 2722G>C, 0.004; 2104C>T, 0.031). CONCLUSION: The 3 most common CD NOD2 mutations do not contribute to disease susceptibility to AS, and therefore do not explain the susceptibility locus for AS in chromosome 16q.

Carrier Proteins↗
PubMed2002

Point mutations in the flanking regions of the Y-chromosome specific STRs DYS391, DYS437 and DYS438.

Sequence analysis of the DNA fragments amplified with the DYS391, DYS437 and DYS438 primers allowed the detection of biallelic polymorphisms in the flanking region of these STR loci. In this work, we describe a methodology where both the STR alleles and the SNPs at these loci are typed. Sequencing of chimpanzee (Pan troglodytes) homologous loci was performed and the ancestral state of the SNPs was determined. The allele distribution of these biallelic markers was analysed within different haplogroups. For DYS391, allele 1 was found in all samples from haplogroups E3a and E* (xE3a). DYS437 allele 1 was present in all haplogroup E3a samples and absent in the haplogroup E* (xE3a). The presence of allele 1 of DYS438 was restricted to haplogroup J. The SNP typing can be helpful in distinguishing STR haplotype identity by descent from identity by state, thus proving to be very informative in forensic investigations.

Animals↗
PubMed2002

The making of the African mtDNA landscape.

Africa presents the most complex genetic picture of any continent, with a time depth for mitochondrial DNA (mtDNA) lineages >100,000 years. The most recent widespread demographic shift within the continent was most probably the Bantu dispersals, which archaeological and linguistic evidence suggest originated in West Africa 3,000-4,000 years ago, spreading both east and south. Here, we have carried out a thorough phylogeographic analysis of mtDNA variation in a total of 2,847 samples from throughout the continent, including 307 new sequences from southeast African Bantu speakers. The results suggest that the southeast Bantu speakers have a composite origin on the maternal line of descent, with approximately 44% of lineages deriving from West Africa, approximately 21% from either West or Central Africa, approximately 30% from East Africa, and approximately 5% from southern African Khoisan-speaking groups. The ages of the major founder types of both West and East African origin are consistent with the likely timing of Bantu dispersals, with those from the west somewhat predating those from the east. Despite this composite picture, the southeastern African Bantu groups are indistinguishable from each other with respect to their mtDNA, suggesting that they either had a common origin at the point of entry into southeastern Africa or have undergone very extensive gene flow since.

Africa↗
PubMed2002

Paternity Testing Commission of the International Society of Forensic Genetics: recommendations on genetic investigations in paternity cases.

The International Society for Forensic Genetics (ISFG) has established a Paternity Testing Commission (PTC) with the purpose of formulating international recommendations concerning genetic investigations in paternity testing. The PTC recommends that paternity testing be performed in accordance with the ISO 17025 standards. The ISO 17025 standards are general standards for testing laboratories and the PTC offers explanations and recommendations concerning selected areas of special importance to paternity testing.

Equipment and Supplies↗
PubMed2002

STR data for the AmpFlSTR Profiler Plus loci from Greece.

Allele frequencies for the nine STRs included in the AmpFlSTR Profiler Plus kit (D3S1358, VWA, FGA, D8S1179, D21S11, D18S51, D5S818, D13S317 and D7S820) were estimated from a sample of 143 unrelated individuals living in different regions of Greece.

Gene Frequency↗
PubMed2002

Chimpanzee homologous of human Y specific STRs. A comparative study and a proposal for nomenclature.

Eleven Y specific microsatellites, previously studied in humans, were typed for fragment length and sequenced in chimpanzees (Pan troglodytes). The primers described by Ayub et al. (Nucleic Acids Res. 28, 2000, 2) for amplifying DYS434, DYS435, DYS436, DYS437, DYS438, DYS439 and those described by White et al. (Genomics, 57, 1999, 433) for GATA A10, A7.1, A7.2, C4, and H4, were used to amplify DNA samples from chimpanzees. Primers described for Y GATA A4 were found to amplify the same region as reported for DYS439. Moreover, the GATA A4 forward primer only matches the repeat flanking region in 14 of the 28bp, being responsible for a very weak amplification. Therefore, this system was not included in this study. The analysis of the repeat and sequence structure observed in chimpanzee and human Y chromosomes allowed evolutionary comparisons as well as the basis for improving Y STR nomenclature and therefore, a unified nomenclature for these novel STRs is proposed to the scientific community following ISFG recommendations.

Animals↗
PubMedDate not supplied

Genetic admixture in three Mexican Mestizo populations based on D1S80 and HLA-DQA1 loci.

This study compares genetic polymorphisms at the D1S80 and HLA-DQA1 loci in three Mexican Mestizo populations from three large states (Nuevo León, Jalisco, and the Federal District). Allele frequency distributions are relatively homogenous in the three samples; only the Federal District population shows minor differences of the HLA-DQA1 allele frequencies compared with the other two. In terms of genetic composition, these Mestizo populations show evidence of admixture with predominantly Spanish-European (50-60%) and Amerindian (37-49%) contributions; the African contribution (1-3%) is minor. Together with the observation that in Nuevo León, the admixture estimates based on D1S80 and HLA-DQA1, are virtually the same as those reported earlier from blood group loci, suggests that DNA markers, such as D1S80 and HLA-DQA1 are useful for examining genetic homogeneity/heterogeneity across Mestizo populations of Mexico. The inverse relationship of the proportion of gene diversity due to population differences (Gst) to within population gene diversity (Hs) is also consistent with theoretical predictions, supporting the use of these markers for population genetics studies.

DNA↗
PubMedDate not supplied

Behavior of loci D1S1656 and D12S391 in a sample from Maracaibo, Venezuela.

Two recently reported short tandem repeat polymorphisms characterized by PCR, D1S1656 and D12S391, were investigated in a sample from Maracaibo, an admixed population of Venezuela, in order to evaluate their application in forensic and population genetics studies. The unbiased heterozygosities were 0.9011 and 0.8444 for locus D1S1656 and D12S391, respectively. The joint discrimination power and joint probability of exclusion were 0.99972 and 0.93287. When allele frequencies of locus D1S1656 from Maracaibo were compared with eight other populations, our group clustered with the European or European-derived samples, mainly from Spain. In the comparison of locus D12S391 with 16 populations, Maracaibo clustered with 3 Asian samples. The high heterozygosity and discrimination power make these two loci important candidates to be considered for STR packages for forensic and population genetic purposes.

Alleles↗