PubMed Health⌕ Search

Biomedical subjects

B R Seizinger

Publications and source records attributed to B R Seizinger.

At least 73 records · Page 4Linked to original sources
PubMed1989

Characterization of a translocation within the von Recklinghausen neurofibromatosis region of chromosome 17.

The genetic defect causing von Recklinghausen neurofibromatosis (NF1) has been mapped to the proximal long arm of chromosome 17 by linkage analysis. Flanking markers have been identified, bracketing NF1 in 17q11.2 and laying the foundation for isolating the disease gene. Recently, a family in which a mother and her two children show both the symptoms of NF1 and the presence of a balanced translocation, t(1;17)(p34.3;q11.2), has been identified. We have examined the possibility that the translocation has occurred in or near the NF1 gene by constructing a somatic cell hybrid line containing the derivative chromosome 1 (1qter-p34.3::17q11-qter). On chromosome 1, the breakpoint occurred between SRC2 and D1S57, which are separated by 14 cM. The translocation breakpoint was localized on chromosome 17 between D17S33 and D17S57, markers that also flank NF1 within a region of 4 cM. These data are consistent with the possibility that the translocation event is the cause of NF1 in this pedigree. Consequently, the isolation of the translocation breakpoint, by approach from either the chromosome 1 or the chromosome 17 side, may facilitate the identification of the NF1 gene.

Animals↗
PubMed1989

Flanking markers for the gene causing von Recklinghausen neurofibromatosis (NF1).

The defective gene causing von Recklinghausen neurofibromatosis (NF1), one of the most common inherited disorders affecting the human nervous system, was recently mapped to chromosome 17. We have used additional DNA markers to further narrow and bracket the NF1 defect. A multipoint linkage analysis suggests that the NF1 gene is flanked by D17Z1 on the centromeric side and by EW 207 on the telomeric side of the long arm of chromosome 17. The identification of closely linked flanking markers should allow us to develop a reliable prenatal and presymptomatic diagnostic test for this serious neurological disorder and provides the basis for applying chromosome-specific cloning techniques for the isolation and characterization of the mutant gene.

Chromosome Mapping↗
PubMed1989

Fundamental mechanisms of tumorigenesis in the human nervous system: isolation and characterization of genes associated with hereditary forms of cancer.

Many human cancers are known to occur in two different forms: as sporadic tumors in the general population and as hereditary tumors within families. Hereditary cancer syndromes offer unique model systems for isolating genes whose mutations lead to cancer. Here I briefly outline "reverse genetics" strategies for the isolation of the defective genes associated with three hereditary tumor syndromes of the human nervous system: neurofibromatosis type 1 (von Recklinghausen's disease) and type 2, and von Hippel-Lindau disease. The cloning and characterization of these genes will have important implications for diagnosis and treatment, not only for the relatively rare hereditary tumors, but also for their much more common sporadic counterparts such as the majority of sporadic brain tumors and renal-cell carcinomas.

Angiomatosis↗
PubMed1988

Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma.

Von Hippel-Lindau disease (VHL) is an autosomal dominant disorder with inherited susceptibility to various forms of cancer, including hemangioblastomas of the central nervous system, phaeochromocytomas, pancreatic malignancies, and renal cell carcinomas. Renal cell carcinomas constitute a particularly frequent cause of death in this disorder, occurring as bilateral and multifocal tumours, and presenting at an earlier age than in sporadic, non-familial cases of this tumour type. We report here that the VHL gene is linked to the locus encoding the human homologoue of the RAF1 oncogene, which maps to chromosome 3p25 (ref. 4). Crossovers with the VHL locus suggest that the defect responsible for the VHL phenotype is not a mutation in the RAF1 gene itself. An alternative or prior event to oncogene activation in tumour formation may be the inactivation of a putative 'tumour suppressor' which can be associated with both the inherited and sporadic forms of the cancer. Sporadic renal cell carcinomas have previously been associated with the loss of regions on chromosome 3p (refs 5, 6). Consequently, sporadic and VHL-associated forms of renal cell carcinoma might both result from alterations causing loss of function of the same 'tumour suppressor' gene on this chromosome.

Angiomatosis↗
PubMed1987

Genetic linkage of von Recklinghausen neurofibromatosis to the nerve growth factor receptor gene.

von Recklinghausen neurofibromatosis (VRNF) is one of the most common inherited disorders affecting the human nervous system. VRNF is transmitted as an autosomal dominant defect with high penetrance but variable expressivity. The disorder is characterized clinically by hyperpigmented patches of skin (café au lait macules, axillary freckles) and by multiple tumors of peripheral nerve, spinal nerve roots, and brain (neurofibromas, optic gliomas). These tumors can cause disfigurement, paralysis, blindness, and death. We have determined the chromosomal location of the VRNF gene by genetic linkage analysis using DNA markers. The VRNF gene is genetically linked to the locus encoding nerve growth factor receptor, located on the long arm of chromosome 17 in the region 17q12----17q22. However, crossovers with the VRNF locus suggest that a mutation in the nerve growth factor receptor gene itself is unlikely to be the fundamental defect responsible for the VRNF phenotype.

Chromosome Mapping↗
PubMed1987

Common pathogenetic mechanism for three tumor types in bilateral acoustic neurofibromatosis.

Bilateral acoustic neurofibromatosis (BANF) is a genetic defect associated with multiple tumors of neural crest origin. Specific loss of alleles from chromosome 22 was detected with polymorphic DNA markers in two acoustic neuromas, two neurofibromas, and one meningioma from BANF patients. This indicates a common pathogenetic mechanism for all three tumor types. The two neurofibromas were among three taken from the same patient, and both showed loss of identical alleles demonstrating that the same chromosome suffered deletion in both tumors. The third neurofibroma from this patient showed no detectable loss of heterozygosity, which suggests the possibility of a more subtle mutational event that affects chromosome 22. In the two acoustic neuromas, only a portion of chromosome 22 was deleted, narrowing the possible chromosomal location of the gene that causes BANF to the region distal to the D22S9 locus in band 22q11. The identification of progressively smaller deletions on chromosome 22 in these tumor types may well provide a means to clone and characterize the defect.

Alleles↗
PubMed1987

Linkage analysis in von Recklinghausen neurofibromatosis (NF1) with DNA markers for chromosome 17.

The mutant gene causing von Recklinghausen neurofibromatosis (NF1) was recently shown to map to chromosome 17. We have used additional markers for chromosome 17 to narrow further the location of the gene defect. A preliminary multipoint linkage analysis suggests that the NF1 gene is located on the long arm of chroomsome 17, flanked by D17Z1 and NGFR. Linkage analysis with the human oncogene homolog erbA1, which maps to this region, suggests that this cancer-related gene is not the primary cause of NF1.

Chromosomes, Human, Pair 17↗
PubMed1987

Molecular genetic approach to human meningioma: loss of genes on chromosome 22.

A molecular genetic approach employing polymorphic DNA markers has been used to investigate the role of chromosomal aberrations in meningioma, one of the most common tumors of the human nervous system. Comparison of the alleles detected by DNA markers in tumor DNA versus DNA from normal tissue revealed chromosomal alterations present in primary surgical specimens. In agreement with cytogenetic studies of cultured meningiomas, the most frequent alteration detected was loss of heterozygosity on chromosome 22. Forty of 51 patients were constitutionally heterozygous for at least one chromosome 22 DNA marker. Seventeen of the 40 constitutionally heterozygotic patients (43%) displayed hemizygosity for the corresponding marker in their meningioma tumor tissues. Loss of heterozygosity was also detected at a significantly lower frequency for markers on several other autosomes. In view of the striking association between acoustic neuroma and meningioma in bilateral acoustic neurofibromatosis and the discovery that acoustic neuromas display specific loss of genes on chromosome 22, we propose that a common mechanism involving chromosome 22 is operative in the development of both tumor types. Fine-structure mapping to reveal partial deletions in meningiomas may provide the means to clone and characterize a gene (or genes) of importance for tumorigenesis in this and possibly other clinically associated tumors of the human nervous system.

Brain Neoplasms↗
PubMed1987

DNA linkage analysis in Von Recklinghausen neurofibromatosis.

We have used DNA linkage analysis in 11 families with Von Recklinghausen neurofibromatosis (VRNF) in order to search for the chromosomal localisation of the defective gene causing this serious neurological disorder. Three groups of polymorphic DNA markers were used: (1) markers for chromosome 22, because of possible allelic genetic heterogeneity between VRNF and bilateral acoustic neurofibromatosis; (2) markers near the centromere of chromosome 4, since there was preliminary evidence for linkage between the VRNF gene and Gc; and (3) oncogenes and growth factors as possible candidate genes for VRNF. Our data exclude close linkage between any of these markers and the gene for VRNF.

DNA↗
PubMed1987

Models for inherited susceptibility to cancer in the nervous system: a molecular-genetic approach to neurofibromatosis.

Neurofibromatosis (NF) is one of the most frequent and clinically important Mendelian disorders in man, with an incidence of 1 in 3,000. While different organ systems and cell types can be affected in NF, the most common abnormalities are in cells of neural crest origin. Two distinct forms of NF have been described: 'peripheral' or von Recklinghausen NF (VRNF) and 'central' or bilateral acoustic NF (BANF). VRNF is characterized clinically by hyperpigmented patches of skin and multiple tumors of the peripheral and central nervous system, which can cause disfigurement, paralysis, blindness and death. In comparison, BANF is characterized by the bilateral occurrence of acoustic neurinomas (Schwann cell-derived tumors of the 8th cranial nerve) and increased susceptibility to certain other nervous system tumors, including meningiomas and gliomas. These tumors can lead to deafness and other serious neurological morbidity and mortality within the first few decades of life. The primary biochemical defects in both forms of NF is not yet known, but is of great fundamental interest in view of the potential role of these genes in controlling proliferation and differentiation of neural crest cells. Here we discuss different molecular-genetic approaches towards identifying these defective genes. In particular, our studies on tumors associated with BANF have specifically implicated chromosome 22 as the location of the gene defect causing this serious neurological disorder. The identification and characterization of the NF genes, based on their chromosomal localizations, will have profound implications for diagnosis and treatment of these diseases and might yield significant insights into mechanisms controlling development and differentiation of the human nervous system.

Chromosome Aberrations↗
PubMed1986

Opioid peptides in Huntington's disease: alterations in prodynorphin and proenkephalin system.

The concentrations of dynorphin A1-8 and Met-enkephalin-Arg6-Gly7-Leu8 were measured in the basal ganglia of postmortem brains from patients with Huntington's disease (HD) and from control subjects. A significant reduction of dynorphin A1-8 concentration was found in caudate nucleus, putamen, external globus pallidus and substantia nigra of HD brains. Levels of Met-enkephalin-Arg6-Gly7-Leu8 were reduced in HD caudate nucleus, putamen, internal and external globus pallidus. These data indicate that both the prodynorphin and proenkephalin opioid peptide system are affected in the basal ganglia in HD.

Basal Ganglia↗
PubMed1986

Isolation and structure of a C-terminally amidated nonopioid peptide, amidorphin-(8-26), from bovine striatum: a major product of proenkephalin in brain but not in adrenal medulla.

We have isolated and sequenced a C-terminally amidated peptide from bovine striatum. The peptide was purified to homogeneity by adsorption to XAD-2 resins and four different HPLC steps. Amino acid composition analysis and gas-phase sequence analysis revealed identity of this peptide with residues 8-26 of the proenkephalin-derived opioid peptide amidorphin, which we have recently isolated from bovine adrenal medulla. C-terminal amidation of amidorphin-(8-26) from bovine striatum was demonstrated by its stability to carboxypeptidase A digestion and full crossreactivity in a radioimmunoassay that required the C-terminal amide group as part of the recognition site. The nonopioid peptide amidorphin-(8-26), which lacks the N-terminal [Met]enkephalin sequence of amidorphin, is a major product of the opioid peptide precursor proenkephalin in the brain. In the adrenal medulla, however, where amidorphin occurs in remarkably high concentrations, amidorphin-(8-26) could not be detected. This is indicative of differential post-translational processing of proenkephalin in different tissues. In the brain, as opposed to the adrenal medulla, amidorphin is further processed at the typical cleavage signals of two basic residues, giving rise to the nonopioid peptide amidorphin-(8-26) and, possibly, to the opioid peptide [Met]enkephalin. Thus, proenkephalin in the brain might be considered as a precursor in which an opioid peptide is linked with a nonopioid peptide of possibly different biological function.

Adrenal Medulla↗
PubMed1985

Characterization of proenkephalin B-derived opioid peptides in the human hypothalamo-neurohypophyseal axis.

Proenkephalin B-derived opioid peptides, such as dynorphin1-17, dynorphin1-8, dynorphin B, alpha-neo-endorphin and beta-neo-endorphin in the human hypothalamo-neurohypophyseal tract were quantitated and characterized by the combined use of various radioimmunoassays, gel filtration, high performance liquid chromatography and enzymatic cleavage. Chromatographic analysis of immuno-reactive peptide levels determined that, in each case, these were comprised almost exclusively of the authentic peptides both in the neurohypophysis and hypothalamus. Concentrations of authentic proenkephalin B-peptides were 100-5000-fold lower in the human as compared to the rat neurohypophysis. However, in the paraventricular nucleus (PVN), supraoptic nucleus (SON) and certain other nuclei of the human hypothalamus concentrations of authentic peptides were found to be in the same range as those in the rat hypothalamus. The ratio of proenkephalin B-peptides in PVN and SON to those of the neurohypophysis in the rat was ca. 1:50. Conversely, in man these ratios were shown to be 80:1 for dynorphin B, 6:1 for alpha-neo-endorphin and 1:1 for all other peptides evaluated. Examination of postmortem degradation of peptides indicated that these lower levels in the neurohypophysis are not due to a higher rate of postmortem breakdown. Since levels of both vasopressin and beta-endorphin were very high, these deficits in proenkephalin B-peptides were selective and do not represent a generalized property of the human pituitary. Experiments involving enzymatic cleavage demonstrated the occurrence of higher molecular weight forms containing the Leu-enkephalin sequence which were not recognized by the antisera employed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Novel opioid peptide amidorphin: characterization and distribution of amidorphin-like immunoreactivity in bovine, ovine, and porcine brain, pituitary, and adrenal medulla.

We have recently isolated from bovine adrenal medulla a novel C-terminally amidated opioid peptide, amidorphin, which derives from proenkephalin A. Amidorphin revealed a widespread distribution in bovine, ovine, and porcine tissue. Particularly high concentrations of amidorphin immunoreactivity were detected in adrenal medulla, posterior pituitary, and striatum, similar to the major gene products of proenkephalin A. In the adrenal medulla of each species, authentic amidorphin was the predominant immunoreactive form. Pituitary and brain, however, contained predominantly putative N-terminally shortened fragments of amidorphin of a slightly lower molecular weight and shorter retention times on HPLC. In addition, in ovine adrenal medulla, a putative high-molecular-weight form of amidorphin was detected. These findings are indicative of a tissue-specific processing of the proenkephalin A precursor, leading predominantly to authentic amidorphin in the adrenal medulla and further processing to smaller C-terminal fragments in the brain and pituitary.

Adrenal Medulla↗