Presymptomatic genetic testing for the presence of a mutant allele causing familial adenomatous polyposis coli (APC) has been difficult to perform effectively in the past because DNA markers surrounding the APC gene on chromosome 5q have not been very informative. We report results of genetic linkage studies on both research families and clinical families by using D5S346, a highly polymorphic dinucleotide (CA)-repeat locus 30-70 kb from the APC gene. Linkage analysis with this marker in a large APC pedigree showed an increase of at least 9.0 LOD units, in likelihood of linkage of the disease-causing allele to the APC locus, when compared with the highest LOD score attained with any other closely linked marker. When the first 14 APC families that requested genotypic analysis by the DNA Diagnostic Laboratory at the University of Utah were tested with D5S346, 20 of the 31 at-risk individuals were identified as either carriers or noncarriers of an APC-predisposing allele. We see this marker as an important tool for research studies and for the presymptomatic diagnosis of APC.

Adenomatous Polyposis Coli↗

PubMed1993

Genetic heterogeneity in benign familial neonatal convulsions: identification of a new locus on chromosome 8q.

The syndrome of benign familial neonatal convulsions (BFNC) is a rare autosomal dominant disorder characterized by unprovoked seizures in the first few weeks of life. One locus for BFNC has been mapped to chromosome 20 in several pedigrees, but we have excluded linkage to chromosome 20 in one large kindred. In order to identify this novel BFNC locus, dinucleotide repeat markers distributed throughout the genome were used to screen this family. Maximum pairwise LOD scores of 4.43 were obtained with markers D8S284 and D8S256 on chromosome 8q. Multipoint analysis placed the BFNC locus in the interval spanned by D8S198-D8S274. This study establishes the presence of a new BFNC locus and confirms genetic heterogeneity of this disorder.

Base Sequence↗

PubMed1993

Linkage disequilibrium in the neurofibromatosis 1 (NF1) region: implications for gene mapping.

To test the usefulness of linkage disequilibrium for gene mapping, we compared physical distances and linkage disequilibrium among eight RFLPs in the neurofibromatosis 1 (NF1) region. Seven of the polymorphisms span most of the NF1 gene, while the remaining polymorphism lies approximately 70 kb 3' to a stop codon in exon 49. By using Centre d'Etude du Polymorphisme Humain (CEPH) kindreds, 91-110 unrelated parents were genotyped. A high degree of disequilibrium is maintained among the seven intragenic polymorphisms (r > .82, P < 10(-7)), even though they are separated by as much as 340 kb. The 3' polymorphism is only 68 kb distal to the next polymorphism, but disequilibrium between the 3' polymorphism and all others is comparatively low (magnitude of 4 < .33, P values .27-.001). This result was replicated in three sets of unrelated kindreds: the Utah CEPH families, the non-Utah CEPH families, and an independent set of NF1 families. Trigenic, quadrigenic, three-locus, and four-locus disequilibrium measures were also estimated. There was little evidence of higher-order linkage disequilibrium. As expected for a disease with multiple mutations, no disequilibrium was observed between the disease gene and any of the RFLPs. The observed pattern of high disequilibrium within the gene and a loss of disequilibrium 3' to the stop codon could have implications for gene mapping studies. These are discussed, and guidelines for linkage disequilibrium studies are suggested.

Chromosome Mapping↗

PubMed1992

Viral (polyomavirus) cystitis heralding cytomegalovirus infection.

Explore the source record for details and available documents.

Adult↗

PubMed1992

Somatic mutations in the neurofibromatosis 1 gene in human tumors.

The neurofibromatosis 1 (NF1) gene product, neurofibromin, contains a GTPase-activating protein (GAP)-related domain, or NF1 GRD, that is able to down-regulate p21ras by stimulating its intrinsic GTPase. Since p21ras.GTP is a major regulator of growth and differentiation, mutant neurofibromins resulting from somatic mutations in the NF1 gene might interfere with ras signaling pathways and contribute to the development of tumors. We describe an amino acid substitution in the NF1 GRD, altering Lys-1423, that has occurred in three tumor types: colon adenocarcinoma, myelodysplastic syndrome, and anaplastic astrocytoma, and in one family with neurofibromatosis 1. The GAP activity of the mutant NF1 GRD is 200- to 400-fold lower than that of wild type, whereas binding affinity is unaffected. Thus, germline mutations in NF1 that cause neurofibromatosis 1 can also occur in somatic cells and contribute to the development of sporadic tumors, including tumors not associated with neurofibromatosis 1.

Adenocarcinoma↗

PubMed1992

Mutations of the 22- and 27-kD zein promoters affect transactivation by the Opaque-2 protein.

By utilizing a homologous transient expression system, we have demonstrated that the Opaque-2 (O2) gene product O2 confers positive trans-regulation on a 22-kD zein promoter. This trans-acting function of the O2 protein is mediated by its sequence-specific binding to a cis element (the O2 target site) present in the 22-kD zein promoter. A multimer of a 32-bp promoter fragment containing this O2 target site confers transactivation by O2. A single nucleotide substitution in the O2 target sequence not only abolishes O2 binding in vitro, but also its response to transactivation by O2 in vivo. We have also demonstrated that an amino acid domain including the contiguous basic region and the heptameric leucine repeat is essential for the trans-acting function of the O2 protein. Similar but not identical O2 target sequence motifs can be found in the promoters of zein genes of different molecular weight classes. Conversion of such a motif in the 27-kD zein promoter to an exact O2 target sequence by site-directed mutagenesis was sufficient to increase the binding affinity of the O2 protein in vitro and to confer transactivation by O2 in vivo.

Base Sequence↗

PubMed1991

Osteochondrodysplasia with rhizomelia, platyspondyly, callosal agenesis, thrombocytopenia, hydrocephalus, and hypertension.

A female infant born at term to phenotypically normal nonconsanguinous parents had hypertension, thrombocytopenia, hydrocephalus, callosal agenesis, and nonlethal rhizomelic osteochondrodysplasia. Her osteochondrodysplasia was characterized roentgenographically by shortening and metaphyseal broadening of long bones, without bowing, and by platyspondyly, with deficient ossification of dorsal and central portions of vertebral bodies. By light microscopy, the iliac crest growth plate showed expansion of the zone of chondrocyte hypertrophy and degeneration, with faulty columnar alignment, sparse vascular ingrowth, and irregular mineralization at the zone of chondroosseous transformation. These findings appear to define a novel osteochondrodysplasia, which in association with hypertension, thrombocytopenia, hydrocephalus, and callosal agenesis may constitute a new syndrome.

Agenesis of Corpus Callosum↗

PubMed1991

A new allele of the duplicated 27kD zein locus of maize generated by homologous recombination.

The 27kD zein storage protein locus in many inbred lines of maize consists of a tandem duplication of 12kb, with an expressed gene in each repeat, termed A and B. A single-copy allele with only the A gene can be generated from this duplication in particular stocks of the maize inbred line A188 by a mitotic process that includes a crossover at the 3' regions of the two genes (1). Here, we characterize a second single-copy allele with only the B gene, found in different stocks of A188. This allele arises from a homologous recombination at the highly conserved 5' regions of the two repeats, and cloning and sequencing of this allele define the crossover region. The A and B genes in the duplicated allele were previously shown to be expressed at different levels; this difference remains unchanged in either recombinant allele. Therefore, the crossover points of these two recombinant alleles define the borders of cis-acting sequences responsible for the differential expression of the two genes.

Alleles↗

PubMed1991

Multiple coronary artery aneurysms in an adult associated with extensive thrombus formation resulting in acute myocardial infarction: successful treatment with intracoronary urokinase, intravenous heparin, and oral anticoagulation.

A 37-yr-old white female was admitted to hospital with an evolving anterior myocardial infarction. Coronary arteriography revealed multiple aneurysms in the left anterior descending (and right) coronary arteries. In the left anterior descending artery, there was evidence of extensive thrombus formation. The patient was successfully treated with intracoronary urokinase, intravenous heparin, and oral warfarin. There was partial thrombolysis in 16 hr and complete thrombolysis noted 6 wk later. This case of multiple coronary aneurysms, secondary to presumed Kawasaki disease, is the first documentation of antemortem intra-aneurysmal coronary thrombosis treated successfully by thrombolytic and anticoagulant therapy.

Administration, Oral↗

PubMed1991

Rotational ablation of chronic coronary occlusions.

Rotational ablation was performed successfully in three chronic coronary occlusions. At 3 months follow-up, two of the three lesions were patent. These cases illustrate the overall advantages and unique technical aspects of this device.

Adult↗

PubMed1991

Sequence variation between alleles reveals two types of copy correction at the 27-kDa zein locus of maize.

In many inbred lines of maize, two 27-kDa storage protein (zein) genes are found within tandem duplications of 12 kb. Both genes of the duplicated allele from the maize inbred line A188 were sequenced and compared to a similar duplicated allele in another inbred line, W22, and to a single-copy allele in the inbred line W64A. The comparisons reveal interesting patterns in the distribution of sequence changes between these alleles. Differences between the two duplicated alleles that are conserved between the two genes of each allele are found exclusively in the 5' region. In contrast, differences between the individual genes of each allele in the 3' region are conserved between the two alleles. The first case is indicative of an intraallelic copy correction mechanism, whereas the second may result from interallelic copy correction. These may be mediated by gene conversion processes, as previously described for other multigene families.

Alleles↗

PubMed1991

A chest radiograph scoring system in adult cystic fibrosis: correlation with pulmonary function.

The Birmingham scoring system for chest radiographs was assessed in 40 adult cystic fibrosis patients, with particular reference to correlation with pulmonary function values. Forty 'initial' and forty 'follow-up' chest radiographs were scored. The mean initial age of the group was 17.5 +/- 5.0 years, and the mean age at follow-up was 23.3 +/- 5.3 years. The cross-sectional radiographic score correlated significantly with the values of three commonly measured, pulmonary function parameters (r = 0.65, 0.67, 0.58, P less than 0.0001). There was a significant correlation (r = 0.64, P less than 0.0001), between the change in radiographic score, and the change in percent predicted forced vital capacity (FVC%). There was a less significant correlation (r = 0.45, P less than 0.006) between the change in radiographic score and the change in per cent predicted forced expiratory volume in one second (FEV1%). We conclude that the Birmingham radiographic scoring system is suitable for quantitative radiological evaluation in adult cystic fibrosis.

Adolescent↗

PubMed1991

A randomized control trial of two cervical spatulas.

The sampling efficacy of the Ayre and Rocket cervical spatulas was compared in a randomized controlled trial involving 533 women who were attending a colposcopy clinic either for investigation of cytological abnormality or for review after treatment of CIN. Smears were compared with respect to the presence of cytological abnormality and two types of normal cervical epithelial cells (endocervical and immature metaplastic cells) which are considered indicators of adequate cytological sampling. Smears taken with the Rocket spatula were significantly less likely to contain immature metaplastic cells (95% CI on difference in proportion; 5-30%), but more likely to contain endocervical cells (95% CI 16-36%). No significant difference was found in the proportion of smears containing one or other type of indicator cell or in the yield of abnormal smears. It is concluded that the Rocket spatula offered no advantage when used in these circumstances. This study illustrates how spurious conclusions of sampling efficacy can be drawn if only one type of indicator cell is used as an endpoint.

Adult↗