Pseudocervical cord syndrome: a deceptive flumazenil reversible manifestation of hepatic encephalopathy.
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Aged↗
Biomedical subjects
D H Gutmann
Publications and source records attributed to D H Gutmann.
Expression of the tuberous sclerosis 2 gene product, tuberin, in adult and developing nervous system tissues.
Tuberous sclerosis (TS) is an autosomal dominant disorder in which affected individuals manifest mental retardation, seizures, and a variety of benign and malignant tumors. The TSC2 tumor suppressor gene was recently identified by positional cloning and its protein product, tuberin, shown to represent one member of the rap GTPase activating protein (rapGAP) family. In order to determine the contribution of tuberin to the development of mental retardation and seizures in patients with TS, we examined the expression of tuberin in adult and developing nervous system tissues. Since tuberin is the second rapGAP found in the nervous system, the expression of tuberin was compared to the expression of rapGAP, rap1, and rap2. In this study, we demonstrate that tuberin is expressed at greatest levels in the spinal cord and cerebellum as opposed to rapGAP, which is not enriched in these tissues. Tuberin expression in the adult CNS is restricted to the olfactory bulb, several CNS neuronal populations, brainstem nuclei, cerebellar Purkinje cells, and motor neurons in the ventral spinal cord. In contrast, rapGAP is expressed in many different cell types in the adult CNS, but not in cerebellar Purkinje cells or motor neurons in the ventral spinal cord. However, there is significant expression of rapGAP in astrocytes. The restricted distribution of tuberin expression relative to rap1 and rapGAP suggests that tuberin may be the primary rap1 regulator in a subpopulation of CNS neurons.
Animals↗
Acute presentation of a neurogenic sarcoma in a patient with neurofibromatosis type 1: a pathological and molecular explanation. Case report.
Neurofibromatosis type 1 (NF1) is the most common familial cancer-predisposing syndrome in humans, for which the gene (NF1) and its gene product (neurofibromin) have been identified. The majority of tumors occurring in patients with NF1 are benign neurofibromas, sarcomatous transformation is uncommon and most often occurs within the larger plexiform neurofibromas. Such malignant transformation in a known neurofibroma is often heralded by either radiological evidence of growth or a progression in clinical symptoms (pain and neurological deficit). This progression in symptoms is usually gradual in onset, typically occurring over a period of months. In this report the authors document a neurogenic sarcoma presenting with rapid clinical and radiological growth. The pathological basis of this acute presentation was increased cellular proliferation, with invasion of blood vessels resulting in tumor infarction. The molecular basis of neurofibroma development in NF1 is loss of expression of the NF1 gene and its gene product, neurofibromin, resulting in elevated levels of Ras-guanosine triphosphate. Subsequent molecular events result in sarcomatous transformation.
Adult↗
Up-regulation of specific NF 1 gene transcripts in sporadic pilocytic astrocytomas.
Pilocytic astrocytomas of the optic nerve (optic nerve gliomas) are closely associated with neurofibromatosis 1 (NF1), and allelic losses of the NF1 gene region on chromosome 17q occur in sporadic pilocytic astrocytomas. We therefore hypothesized that the NF1 gene acts as a tumor suppressor gene in pilocytic astrocytomas, and that NF1 gene expression would be reduced or absent in these tumors. To evaluate this possibility, we examined quantitative and qualitative aspects of NF1 gene expression in six sporadic pilocytic astrocytomas. Surprisingly, the NF1 gene was overexpressed up to fourfold in these tumors when compared with normal brain. This up-regulation was accompanied by immunohistochemical positivity using a carboxyl-terminal antibody and by the absence of mutations in one kilobase of the NF1 coding sequence, consistent with the expressed transcript and protein being full length and probably wild type. Pilocytic astrocytomas showed a marked predominance of transcripts containing exon 23a and lacking exon 9br, the same isoforms that are expressed by normal and reactive astrocytes and malignant astrocytomas. These data illustrate that pilocytic astrocytomas overexpress specific NF1 gene transcripts, perhaps as a regulatory response to growth stimuli. The role of the NF1 gene as a tumor suppressor in pilocytic astrocytomas, however, remains to be proven.
Adolescent↗
Expression of the neurofibromatosis 1 (NF1) gene in reactive astrocytes in vitro.
Neurofibromin, the product of the neurofibromatosis 1 (NF1) gene, is an important tumor suppressor protein expressed most abundantly in the nervous system. Within the central nervous system, neurofibromin has been localized to neurons and oligodendrocytes but not astrocytes. As individuals with NF1 are at an increased risk for optic pathway gliomas and astrocytomas, we chose to re-evaluate the level of neurofibromin expression in primary cultures of murine cortical astrocytes under control and reactive conditions. Astrocytes under control conditions expressed low levels of NF1 mRNA and protein. Following stimulation with dibutyryl-cyclic AMP or interferon-gamma in combination with either lipopolysaccharide or interleukin-1 beta, there was a marked increase in NF1 mRNA and protein expression. These results suggest that neurofibromin may be involved in the process of reactive astrocytosis seen in response to CNS injury.
Animals↗
Oculodentodigital dysplasia with cerebral white matter abnormalities in a two-generation family.
Oculodentodigital dysplasia (ODDD) is an autosomal dominant disorder involving eye and face abnormalities, syndactyly, and enamel hypoplasia. Some individuals with ODDD also have spastic paraparesis. Previously, we reported on a woman with sporadic ODDD and progressive neurologic dysfunction who had cerebral white matter abnormalities demonstrated by magnetic resonance imaging (MRI). We now describe a 2-generation family with ODDD and progressive paraparesis associated with leukodystrophic changes documented by MRI. This family represents one of the largest pedigrees with ODDD described so far. The presence of abnormal white matter changes in both sporadic and inherited forms of ODDD suggests that the phenotype of ODDD should be expanded to include spastic paraparesis.
Abnormalities, Multiple↗
Expression of two new protein isoforms of the neurofibromatosis type 1 gene product, neurofibromin, in muscle tissues.
The neurofibromatosis type 1 (NF1) gene encodes a tumor suppressor protein, termed neurofibromin, which is expressed predominantly in neurons, Schwann cells, oligodendrocytes, and leukocytes. There are at least three isoforms of neurofibromin produced by the alternative use of exons 23a and 48a. Previously we described the identification of an NF1 mRNA isoform containing an additional 54 nucleotides from exon 48a (type 3 NF1) in human skeletal, cardiac and smooth muscle tissues by reverse-transcribed (RT)-PCR. To extend our initial observations, we have produced high titer chicken IgY antibodies which specifically recognize this muscle-specific neurofibromin isoform. An NF1 cDNA was generated containing human exon 48a sequences and expressed as a fusion protein in bacteria. The muscle-specific neurofibromin antibodies detected this exon 48a fusion protein by Western immunoblotting. Immunoprecipitation using these type 3 neurofibromin antibodies also specifically detected a 250 kDa protein in human and rat muscle tissues. Type 3 neurofibromin was found in rat heart and muscle, but not in liver brain, kidney or spleen with levels of expression declining after postnatal day 7. Expression of total NF1 RNA during rat embryonic development was detected at high levels in E15 heart, tongue, and limb bud. In addition, using type 2 neurofibromin-specific antibodies, the existence of a fourth isoform of neurofibromin (type 4 neurofibromin) containing both exon 23a and 48a sequences was demonstrated in rat heart muscle tissues. The identification of two muscle-specific isoforms of neurofibromin expands our definition of this important tumor suppressor protein and suggests additional roles for neurofibromin in muscle development and differentiation.
Amino Acid Sequence↗
Loss of neurofibromatosis type I (NF1) gene expression in pheochromocytomas from patients without NF1.
The neurofibromatosis type 1 (NF1) gene encodes a tumor-suppressor protein termed neurofibromin, which, in adults, is expressed predominantly in neurons, Schwann cells, and the adrenal medulla. Loss of NF1 gene expression has been reported in Schwann cell tumors (neurofibrosarcomas) from patients with NF1 as well as in malignant melanomas and neuroblastomas from patients without NF1. Previously, we demonstrated the lack of neurofibromin expression in six pheochromocytomas from patients with NF1, supporting the idea that neurofibromin might be an essential regulator of cell growth in these cells. To determine whether NF1 gene expression is similarly altered in pheochromocytomas from patients without NF1, we examined 20 pheochromocytomas for the presence of NF1 RNA and neurofibromin by reverse-transcribed polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. Reduced or absent NF1 gene expression was documented in 7 of these 20 tumors (35%) including 1 of 4 sporadic tumors, 3 of 10 tumors from patients with multiple endocrine neoplasia (MEN) 2A, 2 of 4 tumors from patients with MEN2B, and 1 of 2 tumors from patients with von Hippel-Lindau syndrome. In addition, most of these tumors expressed predominantly the type 1 NF1 isoform (75% type 1 NF1 isoform expression) as opposed to other neural crest-derived tissues such as adrenal gland and Schwann cells, which express predominantly type 2 NF1. This type 1 isoform predominance was also observed in the rat pheochromocytoma PC12 cell line, suggesting that this change in isoform expression may be associated with the genesis of these tumors.(ABSTRACT TRUNCATED AT 250 WORDS)
Base Sequence↗
Expression of the neurofibromatosis I gene product, neurofibromin, in blood vessel endothelial cells and smooth muscle.
Vascular pathology is an underestimated complication of neurofibromatosis 1 (NF1). Manifestations include renovascular stenosis with associated hypertension, cerebrovascular occlusion, visceral ischaemia and aneurysms of smaller arteries. This is illustrated by a woman recently evaluated in our Neurofibromatosis Program who had multiple cerebrovascular and renovascular abnormalities. To determine the contribution of NF1 expression to NF1 vasculopathy, the expression of the NF1 gene product, neurofibromin, was examined in blood vessels. Neurofibromin was detected in the endothelial cell layer of rat cerebral vessels, renal arteries, and aorta by immunohistochemistry. Cultured bovine cerebral endothelial cells were found to express NF1 mRNA by RT-PCR and neurofibromin by Western immunoblotting and immunocytochemistry. Neurofibromin expression was also detected in the smooth muscle layer of the aorta but not of cerebral or renal vessels. The vascular abnormalities of NF1 are reviewed and possible pathogenesis with respect to neurofibromin expression is discussed.
Adult↗
Lack of NF1 expression in a sporadic schwannoma from a patient without neurofibromatosis.
The neurofibromatosis type 1 (NF1) gene encodes a tumor suppressor protein, neurofibromin, which is expressed at high levels in Schwann cells and other adult tissues. Loss of NF1 expression has been reported in Schwann cell tumors (neurofibrosarcomas) from patients with NF1 and its loss is associated with increased proliferation of these cells. In this report, we describe downregulation of NF1 expression in a single spinal schwannoma from an individual without clinical features of neurofibromatosis type 1 or 2. Barely detectable expression of NF1 RNA was found in this tumor by in situ hybridization using an NF1-specific riboprobe as well as by Northern blot and reverse-transcribed (RT)-PCR analysis. In Schwann cells cultured from this schwannoma, abundant expression of NF1 RNA could be detected by Northern blot and RT-PCR analysis. These results suggest that, in some tumors, expression of NF1 may be downregulated by factors produced within the tumor and may represent a novel mechanism for inactivating these growth suppressing genes and allowing for increased cell proliferation in tumors.
Adult↗
Expression of the neurofibromatosis type 1 (NF1) gene during mouse embryonic development.
The von Recklinghausen neurofibromatosis type 1 (NF1) gene was identified by positional cloning and found to be a tumor suppressor gene expressed most abundantly in brain. One isoform of NF1 (type 2 NF1) contains an additional 21 amino acids inserted into a region of the protein involved in the regulation of p21-ras. To study the role of the NF1 gene in mammalian development, the expression of the NF1 gene and protein product, neurofibromin, during mouse embryonic development was determined. NF1 mRNA and neurofibromin expression was detectable by Northern and Western analysis, respectively, after day 10 of murine embryogenesis and remained elevated throughout development. Type 2 NF1 mRNA expression predominated before day 10, after which time, type 1 (lacking the insertion) NF1 mRNA was the predominant isoform detected. The protein expression of the type 2 isoform was similar to overall neurofibromin expression by Western blot analysis with greatest expression in adult brain. Despite a similar tissue distribution pattern, type 2 neurofibromin was not found to be associated with brain cytoplasmic microtubules in the same fashion as the uninserted type 1 isoform. Collectively, these experiments suggest that the switch from type 2 to type 1 neurofibromin isoform predominance during embryogenesis may have significant functional consequences.
Animals↗
Expression of the neurofibromatosis 2 (NF2) gene isoforms during rat embryonic development.
The neurofibromatosis 2 (NF2) gene product, merlin, encodes a 595 amino acid protein with sequence similarity to a family of proteins linking cell membrane proteins to the cytoskeleton. Two isoforms of merlin have been described which differ by the presence (type 2 merlin) or absence (type 1 merlin) of exon 16 sequences inserted into the extreme carboxyl terminus of the protein. To determine the role of this important negative growth regulator during normal embryonic development, the expression of these two merlin isoforms was examined at representative stages of rat embryogenesis and in adult tissues. Partial sequence analysis of the rat merlin gene demonstrated striking amino acid identity to the published mouse and human merlin gene sequences. In situ hybridization and RT-PCR analyses demonstrated that rat merlin is widely expressed during embryogenesis and early postnatal life in most tissues but becomes restricted to the brainstem, cerebellum, dorsal root ganglia, spinal cord, adrenal gland and testis in adult animals. The elucidation of the pattern of merlin gene expression in adult and embryonic tissues provides the foundations for future studies aimed at determining the function(s) of this protein during cell differentiation and embryonic development.
Adrenal Glands↗
Expression of the neurofibromatosis 1 (NF1) isoforms in developing and adult rat tissues.
The neurofibromatosis 1 (NF1) gene encodes a large M(r) approximately 250,000 phosphoprotein, the expression of which in adult tissues is limited to neurons, Schwann cells, oligodendrocytes, adrenal medulla, and leukocytes. The presence of two alternatively spliced exons (23a and 48a) in the NF1 gene allow for the generation of four possible neurofibromin isoforms. Type 1 neurofibromin contains neither 23a or 48a exon sequences, while type 2 neurofibromin contains only the 23a exon insertion. Previous studies have demonstrated that types 1 and 2 neurofibromin might have different functional properties relative to microtubule association and GTPase-activating protein activity towards p21-ras. To determine the normal pattern of expression of these NF1 isoforms, the adult and developmental expression of types 1 and 2 NF1 was examined. Herein, we demonstrate that NF1 mRNA is expressed at varying levels in adult tissues and is developmentally regulated during embryogenesis. Neurons in the central nervous system express predominantly type 1 NF1. Using mouse neocortical cultures enriched for neurons or glial cells, type 1 NF1 predominance was demonstrated in neurons, while type 2 NF1 predominated in glial cells. In contrast to central nervous system neurons, neurons expressing the type 2 NF1 isoform were identified in the developing dorsal root ganglia and spinal cord by in situ hybridization using a type 2-specific oligonucleotide probe. The elucidation of the differential expression pattern of these two NF1 isoforms during development and in adult life provides the foundations for future studies aimed at determining the functions of these neurofibromin isoforms.
Animals↗
The tuberous sclerosis 2 gene is expressed at high levels in the cerebellum and developing spinal cord.
Tuberous sclerosis (TS) is an autosomal dominant multisystem disorder characterized by the widespread development of hamartomas in many tissues and organs. TSC2 is predicted to encode a 1784-amino acid tumor suppressor protein that may function, in part, as a GTPase-activating protein for Rap1. Given the high incidence of central nervous system abnormalities in individuals affected with tuberous sclerosis, the expression of TSC2 in developing and adult nervous system tissues was examined. Reverse transcription-PCR, Northern blot, and in situ hybridization analyses demonstrated high levels of expression of TSC2 in the adult brain and developing central nervous system. Abundant TSC2 expression was detected in the adult cerebellum, hippocampus, and olfactory bulb, with lower levels of expression observed in other tissues, including heart and kidney. This enrichment of TSC2 expression in neurons in the central nervous system suggests unique roles for this tumor suppressor gene product in the development and differentiation of nervous system tissues.
Adult↗
Tumor suppressor genes as negative growth regulators in development and differentiation.
Tumor suppressor genes have received much attention for their roles in the development of human malignancies. However, their gene products (proteins) function as negative growth regulators and are highly expressed in many tissues during embryonic development, suggesting that they might function as critical proteins in differentiation and development. The evidence implicating tumor suppressor proteins in cellular differentiation and embryonic development will be presented with special attention to the neurofibromatosis 1, neurofibromatosis 2, and tuberous sclerosis 2 gene products.
Cell Cycle Proteins↗
Modulation of neurofibromatosis type 1 gene expression during in vitro myoblast differentiation.
Neurofibromin, the protein product of the neurofibromatosis type 1 (NF1) gene, has two alternate isoforms which are generated by alternative splicing of two exons. One of these isoforms containing exon 48a is expressed at highest levels in muscle. Since neurofibromin is a p21-ras regulator and has been recently shown to be modulated during Schwann cell differentiation, we examined the expression of the NF1 gene product during in vitro muscle differentiation. Previous work demonstrated that C2C12 murine myoblast cell differentiation could be blocked by the introduction of an activated p21-ras protein. Using this model system, we demonstrate that differentiating C2C12 cells upregulate the expression of NF1 mRNA by 2 days of serum starvation concomitant with increased expression of nicotinic acetylcholine receptor mRNA. This upregulation of mRNA expression paralleled an increase in neurofibromin and N-ras levels, but no change in the relative abundance of the isoforms containing exon 23a or exon 48a was observed during in vitro myoblast differentiation. The increase in neurofibromin levels paralleled a decrease in the levels of activated p21-ras as assayed by in vivo 32P-orthophosphate incorporation into p21-ras. These results suggest that in vitro C2C12 cell differentiation is associated with a concomitant increase in NF1 gene expression and decrease in the proportion of activated p21-ras.
Animals↗
Limitations of magnetic resonance spectroscopy in patients with white matter disease.
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Brain Diseases↗
Loss of neurofibromin in adrenal gland tumors from patients with neurofibromatosis type I.
The neurofibromatosis type I gene encodes a protein, neurofibromin, which may function as a tumor suppressor gene product. Recent studies have demonstrated loss of neurofibromin in tumors from NF1 and non-NF1 patients, including neurofibrosarcomas, neuroblastomas and malignant melanomas. Since neurofibromin is expressed in the adrenal gland, six pheochromocytomas and one adrenal cortical tumor were examined for neurofibromin expression. In all seven tumors, no neurofibromin could be detected. Furthermore, loss of heterozygosity (LOH) analysis demonstrated that in one of the pheochromocytomas, reduction to homozygosity was observed for both 17p and 17q markers while the adrenal cortical tumor demonstrated LOH for only 17q markers. The frequent LOH surrounding the NF1 locus and lack of neurofibromin expression in these tumors suggest that NF1 gene mutations may contribute to the development of adrenal gland neoplasms in patients with NF1.
Adrenal Gland Neoplasms↗