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B R Seizinger

Publications and source records attributed to B R Seizinger.

At least 55 records · Page 3Linked to original sources
PubMed1991

Genetic flanking markers refine diagnostic criteria and provide insights into the genetics of Von Hippel Lindau disease.

Von Hippel Lindau disease (VHL) is a hereditary syndrome, associated with tumors and cysts in multiple organ systems, whose expression and age of onset are highly variable. The availability of a genetic test for the early and reliable detection of individuals carrying the defective gene would be beneficial for VHL patients and their relatives, since many of the manifestations of VHL can be successfully treated if detected in their early stages, while the complications of undetected disease can be devastating. We have previously shown that the VHL gene maps to chromosome 3p. To provide genetic markers for the development of a reliable diagnostic test, and to further narrow and eventually clone the VHL defect, we have generated DNA markers for chromosome 3p. With these markers, we have performed a multipoint genetic linkage analysis in 28 VHL pedigrees, comprising 470 individuals, 164 of whom were affected with VHL. Here we report the identification of tightly linked markers, including flanking markers that bracket the VHL gene to a small region on chromosome 3p25-p26. This finding has several major implications. While visceral cysts of the kidney, pancreas, and epididymis are commonly found in VHL and are considered diagnostic criteria for this disorder, they also occur in the general population. The presence of cysts, unaccompanied by other more typical lesions such as retinal and cerebellar hemangioblastoma, may therefore represent a major diagnostic problem, leading to errors in the assessment of disease status. The application of flanking markers for the VHL gene for presymptomatic diagnostic testing confirms that epididymal cysts are indeed not suitable as a diagnostic criterion in this disorder. Pheochromocytomas occur nonuniformly in VHL families and may also be associated with other hereditary tumor syndromes; our genetic studies imply that the phenotype in VHL families with and without pheochromocytomas is caused by defects within the same gene. The absence or presence of this tumor type is therefore due to the pleiotropic expression of a single gene rather than to the existence of several different genes for VHL. The region on chromosome 3p13-p14 known to contain several chromosomal translocation breakpoints in families with "pure familial renal cell carcinoma" is quite proximal to the VHL locus in 3p25-p26 we have identified. Chromosome 3p may therefore contain two loci for renal cell carcinoma: one gene (or genes) in 3p13-p14 and the VHL gene in 3p25-p26, whose aberration is also associated with other typical manifestations of VHL. Since renal cell carcinoma, pheochromocytoma, and visceral cysts can occur sporadically even in young people and may also be associated with other tumor syndromes, the availability of flanking markers for the VHL gene will be useful in identifying VHL gene carriers, particularly among those individuals at risk in whom these are the only manifestations of disease. The isolation and characterization of the VHL gene, based on the identification of flanking markers, will have important implications for diagnosis and treatment of patients with VHL, as well as for a much larger number of individuals having the sporadic counterparts of VHL-associated tumor types.

Cell Line↗
PubMed1991

Genes associated with tumor suppression and growth control in the human nervous system.

Cancer, the uncontrolled proliferation of a population of somatic cells, is fundamentally a genetic disorder. Although the specific array of genetic changes causing individual tumor types remains largely obscure, the past two decades have witnessed a tremendous increase in our understanding of the specific genes regulating cell differentiation, proliferation, and senescence. There appear to be two distinct fundamental genetic mechanisms of tumorigenesis. One mechanism is associated with the activation of growth-promoting factors such as proto-oncogenes. Alternatively, tumor formation may be induced as the result of the loss or inactivation of genes which normally regulate or suppress cell growth. These genes have been termed 'tumor suppressor' genes or 'anti-oncogenes'. This review focuses on the role of 'tumor suppressor' genes in tumor formation and growth control of the human nervous system.

Central Nervous System↗
PubMed1991

Parental origin of chromosome 22 loss in sporadic and NF2 neuromas.

It has recently been proposed that the maternally derived chromosome might be preferentially lost in nonfamilial cases of embryonal or early onset malignant tumors. This observation pointed to a potential role of the parental imprinting of the genome during gametogenesis which would be at least partly maintained in the somatic cells. Neuromas are benign tumors that develop from Schwann cells. They occur either sporadically or in individuals that have a genetic predisposition due to neurofibromatosis type 2 (NF2) and usually are multiple. Regardless of the context of occurrence, in approximately 40% of the investigated cases a loss of a chromosome 22 has been documented either by karyotype analysis or by monitoring somatic loss of heterozygosity. We have now examined the parental origin of the chromosome 22 lost in 19 cases of neuromas of patients with unaffected parents among which 11 were non-NF2 patients (sporadic and unique neuroma) and 8 were NF2 patients (bilateral acoustic or multiple neuromas). In both sets of tumors, the lost chromosome 22 can be of either parental origin. A close to threefold preference for the loss of the maternally derived chromosome was observed and should be either confirmed or disproved by studying a larger number of patients.

Adult↗
PubMed1991

Toward the isolation of the primary genetic defect in von Hippel-Lindau disease.

Von Hippel-Lindau disease (VHL) is a devastating hereditary tumor syndrome associated with various forms of cancer in multiple organ systems, including endothelial-derived tumors in the central nervous system, pheochromocytomas, and, a particularly frequent cause of death in VHL, renal cell carcinomas. Using DNA linkage analysis in a number of families displaying VHL, we recently showed that the primary defect in VHL maps to the short arm of chromosome 3. On the basis of the approximate knowledge of its chromosomal location, we have meanwhile bracketed this putative "tumor suppressor" gene to a small region of approximately 10 cM in chromosome 3p25-p26. The identification of closely linked flanking markers, together with the apparent genetic homogeneity of VHL, should allow for the development of a reliable diagnostic genetic test and provides the starting point for directed chromosomal "walking" and "jumping" toward the isolation of the defective gene itself. The characterization of the VHL gene should ultimately have important implications not only for patients with VHL, but also for a much larger number of cancer patients in the general population, afflicted with the sporadic counterparts of VHL-associated tumor types, such as renal cell carcinoma.

Chromosomes, Human, Pair 3↗
PubMed1991

Molecular genetics of neurofibromatosis 2 and related tumors (acoustic neuroma and meningioma).

Meningioma and acoustic neuroma are among the most frequent primary tumors of the central nervous system. They usually arise as sporadic and solitary tumors. They also develop as multiple tumors in the autosomal dominant genetic disorder neurofibromatosis 2 (NF2). Molecular analysis of meningioma and acoustic neuroma revealed that loss of chromosome 22 alleles was the most frequent genetic alteration found in either sporadic or inherited cases. Subsequent studies showed that a marker in the middle of the long arm of chromosome 22 was linked to the disease in NF2 pedigrees. In this paper, the most recent findings concerning the genetics of NF2 and related tumors are reviewed, and strategy to isolate and characterize the NF2 gene is presented.

Chromosome Mapping↗
PubMed1991

Central nervous system involvement in Von Hippel-Lindau disease.

Fifty individuals with Von Hippel-Lindau disease (VHL) were studied with gadolinium-enhanced magnetic resonance imaging (MRI) to determine the frequency and distribution of CNS lesions. The associated clinical features were also reviewed. Thirty-six (72%) of the 50 had 1 or more CNS tumors. The most frequently affected sites in the CNS excluding the retina were the cerebellum (52%), spinal cord (44%), and brainstem (18%). New regional predilections for the craniocervical junction and conus medullaris were demonstrated by this study. Forty-one percent of all VHL patients with CNS tumors were neurologically asymptomatic: cerebellar tumors (50%), spinal cord tumors (50%), and brainstem tumors (44%) were often without clinical signs or symptoms. Multiple lesions were common. The mean age of all VHL patients (34.5 years) was similar to the mean age of all CNS VHL patients (34.4 years), suggesting a lack of age association. CNS lesions commonly occurred in the 2nd decade of life. All patients at risk for VHL should be evaluated using gadolinium-enhanced MRI after 10 years of age, although ophthalmic examination should be initiated within the 1st 2 years of life. Enhanced MRI is particularly useful in the detection of CNS tumors in patients with the VHL gene.

Adolescent↗
PubMed1990

Loss of the Y chromosome in meningiomas. A molecular genetic approach.

Loss of the Y chromosome in meningiomas from 17 male patients was examined by cytogenetic analysis and by Southern blot hybridization with a series of Y-specific DNA probes. Cytogenetic analysis revealed loss of the Y chromosome in seven of 17 (41%) of the tumors whereas Southern blot hybridization showed loss of Y-associated sequences in only three of 17 (18%). Although the incidence of Y-chromosome loss was less by Southern blot hybridization than by cytogenetic analysis, the finding that loss of Y is present in the original uncultured tumor specimen suggests that a gene or genes on the Y chromosome may play a role in growth control of meningioma cells, and loss of this gene may be associated with tumor progression. The difference in the incidence of Y loss between the two methods indicates that both methods should be used when examining chromosome losses.

Adult↗
PubMed1990

Progress toward the isolation and characterization of the genes causing neurofibromatosis.

Neurofibromatosis 1 and neurofibromatosis 2 are clinically distinct autosomal dominant disorders that affect an estimated 1.5 million individuals throughout the world. The genetic defect in each disorder has been mapped to different chromosomes, NF1 to chromosome 17 and NF2 to chromosome 22. Progress towards the cloning of the NF1 gene has proceeded rapidly. The NF1 locus was bracketed using genetic linkage analysis on NF1 affected pedigrees. Physical mapping methods were then used to precisely map the translocation breakpoints in each of two NF1 affected individuals who harbored constitutional chromosomal translocations in the putative NF1 region of chromosome 17. The region of DNA located between the two translocations has been cloned in cosmids and yeast artificial chromosomes and a number of RNA coding sequences have been identified. The identification of the NF1 gene will depend on finding mutations in the DNA of affected individuals. In the case of NF2, progress seems to have been less rapid, in part due to the lower availability of NF2 affected pedigrees. The genetic defect has been mapped to the long arm of chromosome 22 by studies of chromosomal loss in the tumours associated with this disease. Subsequent genetic mapping has confirmed this location. Flanking DNA markers for the NF2 locus have been identified. The region of DNA between these markers is in the order of 5-10 Mb. The identification of chromosomal aberrations in patients with NF2 that involve chromosome 22 will play an important role in the identification of the NF2 gene in much the same way as they have in NF1.

Chromosome Aberrations↗
PubMed1990

von Hippel-Lindau disease: radiologic screening for visceral manifestations.

The visceral manifestations of von Hippel-Lindau (VHL) disease can cause significant morbidity and mortality. The authors prospectively screened 37 persons from a single kindred. Twenty-five subjects underwent abdominal ultrasound (US), contrast material-enhanced abdominal computed tomography (CT), and nonenhanced abdominal magnetic resonance (MR) imaging. Eight subjects younger than 16 years of age underwent abdominal US and MR imaging only. Scrotal US was employed in 25 male patients. Eleven subjects had renal cysts or tumors. Contrast-enhanced CT depicted renal abnormalities in 10 of these subjects, US in seven, and MR imaging in nine. Among 12 subjects with pancreatic cysts or tumors, CT showed pancreatic abnormalities in all 12, US in nine, and MR imaging in nine. Three subjects (mean age, 34.5 years) had renal tumors, and three had pancreatic masses. Scrotal US revealed epididymal cystadenomas in seven subjects; two of these tumors were surgically verified. A combination of contrast-enhanced CT and scrotal US in male patients appears to be the best way to screen for visceral manifestations of VHL disease.

Adolescent↗
PubMed1990

Clonal origin of pituitary adenomas.

Benign pituitary adenomas are among the most common neurosurgical tumors and account for a diversity of clinical syndromes due to their hormone content and release. To determine whether these tumors arise from a single cell or multiple cells, the authors studied X chromosome inactivation in deoxyribonucleic acid (DNA) isolated from pituitary adenomas in women. Tumors of three different hormonal subtypes were examined. One tumor contained cells immunoreactive for prolactin and human growth hormone; one tumor contained foci immunoreactive for the beta-subunits of luteinizing hormone and follicle-stimulating hormone; and the third tumor had no immunoreactive prolactin, human growth hormone, beta-subunits of thyroid-stimulating hormone, luteinizing hormone, or follicle-stimulating hormone, or the alpha-subunit. Analysis of the DNA revealed that, in each of the three pituitary tumors, one X chromosome was active in all cells and one X chromosome was inactive, indicating that each of these tumors was monoclonal in origin. It is concluded that clinically evident pituitary tumors arise from a genetic mutation in a single cell.

Adenoma↗
PubMed1990

Flanking markers bracket the neurofibromatosis type 2 (NF2) gene on chromosome 22.

Neurofibromatosis 2 or bilateral acoustic neurofibromatosis (NF2) is a severe autosomal dominant disorder characterized by the development of multiple tumors of the nervous system, including meningiomas, gliomas, neurofibromas, ependymomas, and particularly acoustic neuromas. Polymorphic DNA markers have revealed frequent loss of one copy of chromosome 22 in the tumor types associated with NF2. Family studies have demonstrated that the primary defect in NF2 is linked to DNA markers on chromosome 22, suggesting that it involves inactivation of a tumor suppressor gene. We have employed a combination of multipoint linkage analysis and examination of deletions in primary tumor specimens to precisely map the NF2 locus between flanking polymorphic DNA markers on chromosome 22. The 13-cM region bracketed by these markers corresponds to 13% of the genetic length of the long arm of chromosome 22 and is expected to contain less than 5 x 10(6) bp of DNA. The delineation of flanking markers for NF2 should permit accurate presymptomatic and prenatal diagnosis for the disorder and greatly facilitate efforts to isolate the defective gene on the basis of its location.

Alleles↗
PubMed1990

Progress towards the isolation and characterization of the genes causing neurofibromatosis.

The locus for the gene causing neurofibromatosis type 1 (NF1) was bracketed to a region on the long arm of chromosome 17 by means of genetic linkage analysis. When the limits of resolution for genetic mapping were reached physical mapping methods were used to map the NF1 gene precisely, with reference to translocation breakpoints in NF1 affected individuals who harboured constitutional chromosomal translocations on chromosome 17. The region of DNA located between two translocation breakpoints has been cloned and a DNA sequence encoding a 11-13 kb mRNA identified. That this sequence shows deletions and point mutations in NF1 affected individuals and not in normal controls provides strong evidence that it is indeed the NF1 gene. The genetic defect in NF2 has been mapped to chromosome 22 by studies of chromosomal loss in tumours associated with this disease. Subsequent linkage analysis of NF2 pedigrees has confirmed this location. DNA markers that bracket the NF2 locus to a region of 5-10 Mb have been identified.

Chromosome Mapping↗
PubMed1989

Physical mapping of a translocation breakpoint in neurofibromatosis.

The gene for von Recklinghausen neurofibromatosis (NF1), one of the most common autosomal-dominant disorders of humans, was recently mapped to chromosome 17 by linkage analysis. The identification of two NF1 patients with balanced translocations that involved chromosome 17q11.2 suggests that the disease can arise by gross rearrangement of the NF1 locus, and that the NF1 gene might be identified by cloning the region around these translocation breakpoints. To further define the region of these translocations, a series of chromosome 17 Not I-linking clones has been mapped to proximal 17q and studied by pulsed-field gel electrophoresis. One clone, 17L1 (D17S133), clearly identifies the breakpoint in an NF1 patient with a t(1;17) translocation. A 2.3-megabase pulsed-field map of this region was constructed and indicates that the NF1 breakpoint is only 10 to 240 kilobases away from 17L1. This finding prepares the way for the cloning of NF1.

Chromosome Mapping↗
PubMed1989

Progress towards identifying the neurofibromatosis (NF1) gene.

Von Recklinghausen neurofibromatosis (NF1) is a common autosomal dominant disorder of humans. Linkage analysis has recently mapped the NF1 gene to the proximal long arm of chromosome 17. The identification of two NF1 patients with balanced translocations has now allowed the location of the gene to be narrowed to a few hundred kilobases of chromosome band 17q11.2, using a combination of somatic cell hybrid technology, linking clones and pulsed field gel electrophoresis.

Chromosome Mapping↗