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X Estivill

Publications and source records attributed to X Estivill.

At least 181 records · Page 10Linked to original sources
PubMed1997

Ultrasonographic study of pancreatic cysts in autosomal dominant polycystic kidney disease.

Pancreatic cysts are an uncommon extrarenal clinical feature of autosomal dominant polycystic kidney disease (ADPKD). The prevalence of pancreatic cysts, sonographically assessed in ADPKD and in the different typs of ADPKD (PKD1 and PKD2) has not been reported. We have studied 173 ADPKD patients and 160 non-affected family members and found a prevalence of pancreatic cysts, of 9% in ADPKD patients over 30 years of age. The presence of pancreatic cysts was related to the increasing age, to the female sex and to the type of ADPKD, found exclusively in PKD1 patients. No complications related to pancreatic cysts were recorded. Pancreatic cysts are an unusual feature of ADPKD and do not appear to contribute to morbidity or mortality.

Adolescent↗
PubMed1997

Localization, by linkage analysis, of the cystinuria type III gene to chromosome 19q13.1.

Cystinuria is an autosomal recessive aminoaciduria in which three urinary phenotypes (I, II, and III) have been described. An amino acid transporter gene, SLC3A1 (formerly rBAT), was found to be responsible for this disorder. Mutational and linkage analysis demonstrated the presence of genetic heterogeneity in which the SLC3A1 gene is responsible for type I cystinuria but not for type II or type III. In this study, we report the identification of the cystinuria type III locus on the long arm of chromosome 19 (19q13.1), obtained after a genomewide search. Pairwise linkage analysis in a series of type III or type II families previously excluded from linkage to the cystinuria type I locus (SLC3A1 gene) revealed a significant maximum LOD score (zeta max) of 13.11 at a maximum recombination fraction (theta max) of .00, with marker D19S225. Multipoint linkage analysis performed with the use of additional markers from the region placed the cystinuria type III locus between D19S414 and D19S220. Preliminary data on type II families also seem to place the disease locus for this rare type of cystinuria at 19q13.1 (significant zeta max = 3.11 at theta max of .00, with marker D19S225).

Chromosome Mapping↗
PubMed1996

Genomic structure and organization of the human rBAT gene (SLC3A1).

Cystinuria is an autosomal recessive disorder of amino acid transport, manifesting as three phenotypes (I, II, and III). An amino acid transport gene, rBAT, is responsible for cystinuria. Mutation and linkage analyses have demonstrated the disease to be heterogeneous, with rBAT being the defective gene in type I cystinuria. The genomic structure of the human rBAT gene (HGMW-approved symbol SLC 3A1) has been established via two strategies: (i) construction of two different genomic libraries by subcloning the Mega-YAC921B6 (CEPH), containing rBAT, in Lambda ZAP and screening using rBAT cDNA and different PCR products; and (ii) generation and sequencing of genomic fragments by long PCR using rBAT cDNA-derived primers. The rBAT gene spans approximately 45 kb and consists of 10 exons. The introns range from 500 to 13,000 bp. All splice sites conform to the GT/AG rule. The promoter region has been further analyzed, and a predicted TATA box 98 bp upstream of the first coding ATG was identified. In addition an Alu repeat has been detected 72 bp upstream of the predicted TATA box.

Amino Acid Transport Systems, Basic↗
PubMed1996

[The molecular pathology of RET protooncogene in families with multiple endocrine neoplasia type 2A].

BACKGROUND: Multiple endocrine neoplasm type 2A (MEN 2A) is an autosomal dominantly inherited disease characterized by medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. Mutations have been identified in the extracellular domain of the RET proto-oncogen product (10q11.2) in MEN 2A patients. In each case a single base pair substitution results in replacement of cysteine with another amino acid. Most MEN 2A patients have mutations of codon 634. PATIENTS AND METHODS: Sixty-five unrelated MEN 2A patients from seven families were studied. Polymerase chain reaction, segregation, sequence analysis and restriction enzyme digestion were performed. RESULTS: Of seven families, four had the TGC to TAC transition, two families the TGC to TGG transversion and one family the TGC to CGC transition in codon 634 of RET. CONCLUSIONS: We found all the mutations in codon 634. The characterization of MEN 2A mutations allows early and presymptomatic diagnosis in this syndrome.

Base Sequence↗
PubMed1996

Cloning (CAG/GTC)n STSs by an Alu-(CAG/GTC)n PCR method: an approach to human chromosome 12 and spinocerebellar ataxia 2 (SCA2).

We report here an Alu-(CAG/GTC)n PCR method for the cloning of STSs with (CAG/GTC)n sequences. We have applied this method to genomic DNA of a somatic cell hybrid containing human chromosome 12 where linkage has been found for a known familiar dominant ataxia (SCA2), which is thought to be due to a (CAG/GTC)n expansion. We have isolated several clones containing (CAG/GTC)n sequences, which include previously identified sequences that map to chromosome 12. This method could be a new PCR approach for the cloning of repeats based on their proximity to Alu sequences.

Base Sequence↗
PubMed1996

A nuclear defect in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome.

Wolfram syndrome is a progressive neurodegenerative disorder transmitted in an autosomal recessive mode. We report two Wolfram syndrome families harboring multiple deletions of mitochondrial DNA. The deletions reached percentages as high as 85-90% in affected tissues such as the central nervous system of one patient, while in other tissues from the same patient and from other members of the family, the percentages of deleted mitochondrial DNA genomes were only 1-10%. Recently, a Wolfram syndrome gene has been linked to markers on 4p16. In both families linkage between the disease locus and 4p16 markers gave a maximum multipoint lod score of 3.79 at theta = 0 (P<0.03) with respect to D4S431. In these families, the syndrome was caused by mutations in this nucleus-encoded gene which deleteriously interacts with the mitochondrial genome. This is the first evidence of the implication of both genomes in a recessive disease.

Adult↗
PubMed1996

Prenatal diagnosis of cystic fibrosis in a highly heterogeneous population.

Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasian populations. The Spanish CF population is highly heterogeneous, with more than 70 different mutations causing CF. Since the CFTR gene was cloned, we have performed 81 prenatal diagnoses for 74 couples. Sixty-nine cases had a high risk (1/4) for CF and 12 presented a lower risk (1/240). Direct analysis was possible in 36 cases (44.4 per cent); it was necessary to combine mutation analysis with polymorphic markers in 24 cases (29.6 per cent); mutation analysis and microvillar enzymatic (MVE) analysis were combined in five cases (6.1 per cent); and in 16 cases (19.8 per cent), only indirect analysis was possible. Nine different mutations were detected in this series of families: 621 + 1G -> T, delta F508, 1609delCA, G542X, G551D, 1949del84, R1162X, W1282X, and N1303K. Another ten mutations were identified in these samples after prenatal diagnosis (1811 + 1.6kbA -> G, 711 + 1G -> T, 2869insG, G85E, 2176insC, delta I507, 3272-26A -> G, Q890X, R1066C, and 4005 + 1G -> A). Our current strategy for molecular diagnosis of CF in the Spanish population is based, as a first step, on direct analysis for the two most frequent mutations (delta F508 and G542X) and indirect analysis using the intragenic markers IVS8CA, IVS17BTA, and IVS17BCA. The second step consists of screening for the mutations already associated with the CFTR microsatellite haplotypes. The third step is a specific search for unknown mutations. While actual diagnostic methods are not automatic and robust enough for heterogeneous populations, the diagnostic strategy outlined provides rapid, accurate, and reliable prenatal diagnosis for the majority of couples.

Amniotic Fluid↗
PubMed1996

Haplotype analysis of 94 cystic fibrosis mutations with seven polymorphic CFTR DNA markers.

We have analyzed 416 normal and 467 chromosomes carrying 94 different cystic fibrosis (CF) mutations with polymorphic genetic markers J44, IVS6aGATT, IVS8CA, T854, IVS17BTA, IVS17BCA, and TUB20. The number of mutations found with each haplotype is proportional to its frequency among normal chromosomes, suggesting that there is no preferential haplotype in which mutations arise and thus excluding possible selection for specific haplotypes. While many common mutations in the worldwide CF population showed absence of haplotype variation, indicating their recent origins, some mutations were associated with more than one haplotype. The most common CF mutations, delta F508, G542X, and N1303K, showed the highest number of slippage events at microsatellites, suggesting that they are the most ancient CF mutations. Recurrence was probably the case for 9 CF mutations (R117H, H199Y, R347YH, R347P, L558S, 2184insA, 3272-26A-->G, R1162X, and 3849 + 10kbC-->T). This analysis of 94 CF mutations should facilitate mutation screening and provides useful data for studies on population genetics of CF.

Cystic Fibrosis↗
PubMed1996

Geographic distribution and origin of CFTR mutations in Germany.

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. delta F508 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 delta F508 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.

Cystic Fibrosis↗
PubMed1996

CFTR haplotypic variability for normal and mutant genes in cystic fibrosis families from southern France.

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 polymorphism (IVS6A, IVS8CA, M470V, T854T, IVS17BTA, IVS17BCA and TUB18)] were analyzed for 143 delta F508 chromosomes, 100 CF chromosomes carrying 85 non-delta F508 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-delta F508 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 (delta F508, G542X, N1303K, G85E, E585X, K710X and 2184delA) or recombination (1717-1G-->A, R334W, L206W, R1162X and Y122X). Haplotypes for the most common CFTR mutations (delta F508, 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.

Cystic Fibrosis↗
PubMed1996

A female compound heterozygote (pre- and full mutation) for the CGG FMR1 expansion.

Fragile X syndrome is the most common cause of inherited mental retardation. The incidence has been estimated to be 1 in 1250 males and 1 in 2000 females. Molecular studies have shown that 95% of fragile X syndrome cases are caused by the expansion of a CGG triplet in the FMR1 gene with hypermethylation of the adjacent CpG island. In spite of the high incidence of this syndrome, a female with both FMR1 genes in the expanded form has never been reported. We presenting mental retardation and attention problems. Molecular analysis has revealed that both of her FMR1 genes have the CGG expansion, one with a premutation and the other with a full mutation. We have studied the CGG repeat in the FMR1 gene in 64 members of her family and detected 33 normal individuals, 14 carriers with the premutation (1 male and 13 females), and 18 individuals with full mutations (8 males and 10 females). The index case illustrates that the possibility of both parents being carriers of the fragile X syndrome premutation should be considered in consanguineous families or in small communities.

Adult↗
PubMed1996

Molecular analysis of the cystinuria disease gene: identification of four new mutations, one large deletion, and one polymorphism.

A cystinuria disease gene (rBAT) has recently been identified, but evidence strongly suggests that only Type-I cystinuria is due to mutations in this gene. Sixteen point mutations and a large deletion causing the disease have so far been described in the rBAT gene sequence. To identify new mutated alleles, genomic DNA was analyzed, after the determination of the entire genomic structure of the rBAT gene, by RNA-single strand conformation polymorphism analysis, an accurate and sensitive method able to detect nucleotide changes. Four new point mutations, a large deletion, and a common intragenic polymorphism were detected. These new mutations increase to 22 the number of mutated alleles so far characterized in rBAT. In addition, the frequency of 21 mutations was assessed in a sample of accurately defined Type-I cystinuria chromosomes. They account for about 58% of all Type-I chromosomes, mutation M467T being the most common (0.26).

Alleles↗
PubMed1996

YAC and cosmid FISH mapping of an unbalanced chromosomal translocation causing partial trisomy 21 and Down syndrome.

Most cases of Down syndrome (DS) result from a supernumerary chromosome 21; however, there are rare cases in which DS is due to partial trisomy of chromosome 21, involving various segments of the chromosome. The characterization of cases of DS that are due to partial trisomy 21 allows the phenotype to be correlated with the genotype. We present a case with features of DS and a partial trisomy of chromosome 21 inherited from a paternal balanced translocation involving chromosomes 13 and 21. Fluorescence in situ hybridization analysis using yeast artificial chromosome (YAC) probes mapped the breakpoint to 21q22.1, within YAC 230E8, which contains markers CBR, D21S333 and D21S334. Further mapping using cosmids positioned the breakpoint proximal to CBR. The patient was also monosomic for the distal portion of chromosome 13 (q33-qter). Many phenotypic features of DS were present including hypotonia, flat occiput, flat facies, up-slanted palpebral fissures, epicanthic folds, flat nasal bridge, macroglossia, open mouth, small ears and a heart murmur. This case further supports the contention that the majority of the phenotypic features of DS map to 21q22-qter and further refines the location of some of them. In addition to the DS phenotype, the patient had a prominent upper maxilla with protruding upper incisors, and low levels of the coagulation factors VII and X, consistent with a syndrome resulting from monosomy 13q33-qter. Since some features overlap between the two syndromes, including severe mental retardation, it is unclear to what extent monosmy for 13q33-qter, trisomy for 21q22.1-qter, or a combination of both, contributed to the common features of the phenotype.

Adult↗
PubMed1996

Sex differences in mutational rate and mutational mechanism in the NF1 gene in neurofibromatosis type 1 patients.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a prevalence of around 1 in 3500, affecting all ethnic groups. The clinical manifestations of the disease are variable, even among members of the same family, and affect a variety of tissues and cell types, including skin, iris, central and peripheral nervous systems and skeletal system. It has been reported that the majority of sporadic mutations in NF1 arise in paternally inherited alleles. We present here a collaborative study of the parental origin and type of mutation in individuals with de novo NF1, who account for up to a half of all cases of clinically diagnosed NF1. We have studied intragenic and extragenic markers in 470 NF1 families. In 32 of these families it was possible to assess the parental origin of a de novo NF1 mutation either by linkage analysis (in families with three generations) or by the detection of an intragenic deletion in a sporadic NF1 case. Eleven of these 32 families have three generations (the second and third generation being affected), with the mutation (not a large deletion) being of paternal origin in 82% of them (P < 0.05). In the other 21 families an intragenic deletion was detected, in 76% being in the maternal chromosome and in 24% in the paternal one (P < 0.05). Our results suggest that in NF1 the majority of deletions occur in oogenesis, while other types of mutations should account for the paternally derived NF1 mutations.

Chromosome Mapping↗