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U Suter

Publications and source records attributed to U Suter.

At least 73 records · Page 4Linked to original sources
PubMed1996

Impaired differentiation of Schwann cells in transgenic mice with increased PMP22 gene dosage.

An intrachromosomal duplication containing the PMP22 gene is associated with the human hereditary peripheral neuropathy Charcot-Marie-Tooth disease type 1A, and PMP22 overexpression as a consequence of increased PMP22 gene dosage has been suggested as causative event in this frequent disorder of peripheral nerves. We have generated transgenic mice that carry additional copies of the pmp22 gene to prove that increased PMP22 gene dosage is sufficient to cause PNS myelin deficiencies. Mice carrying approximately 16 and 30 copies of the pmp22 gene display a severe congenital hypomyelinating neuropathy as characterized by an almost complete lack of myelin and marked slowing of nerve conductions. Affected nerves contain an increased number of nonmyelinating Schwann cells, which do not form onion bulbs but align in association with axons. The mutant Schwann cells are characterized by a premyelination-like state as indicated by the expression of embryonic Schwann cell markers. Furthermore, continued Schwann cell proliferation is observed into adulthood. We hypothesize that Schwann cells are impaired in their differentiation into the myelinating phenotype, leading to a disorder comparable to severe cases of hereditary motor and sensory neuropathies. Our findings, combined with the analysis of heterozygous and homozygous PMP22-deficient mice, indicate that aberrant pmp22 gene copy numbers cause various forms of myelination defects.

Animals↗
PubMed1996

A transgenic rat model of Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy in humans and has been associated with a partial duplication of chromosome 17 (CMT type 1A). We have generated a transgenic rat model of this disease and provide experimental evidence that CMT1A is caused by increased expression of the gene for peripheral myelin protein-22 (PMP22, gas-3). PMP22-transgenic rats develop gait abnormalities caused by a peripheral hypomyelination, Schwann cell hypertrophy (onion bulb formation), and muscle weakness. Reduced nerve conduction velocities closely resemble recordings in human patients with CMT1A. When bred to homozygosity, transgenic animals completely fail to elaborate myelin. We anticipate that the CMT rat model will facilitate the identification of a cellular disease mechanism and serve in the evaluation of potential treatment strategies.

Animals↗
PubMed1996

Ultrastructural distribution of PMP22 in Charcot-Marie-Tooth disease type 1A.

Peripheral Myelin Protein-22 (PMP22) is a membrane glycoprotein which represents up to 5% of total protein in myelin of peripheral nerves. Mutations affecting the PMP22 gene have been linked to the inherited peripheral neuropathies Charcot-Marie-Tooth disease type 1A (CMT1A; duplications and point mutations), Dejerine-Sottas syndrome (DSS; point mutations), and hereditary neuropathy with liability to pressure palsies (HNPP; deletions). In this study, we determined the ultrastructural distribution of PMP22 and other myelin proteins in normal human peripheral nervous system (PNS) nerves and in CMT1 patients with or without the CMT1A duplication on chromosome 17. Our results demonstrate that PMP22, P0 protein, and myelin basic protein are present in compact myelin of all patients examined. PMP22 was also present in the plasma membrane of Schwann cells of unmyelinated fibers and onion bulbs. Although the precise biological role of PMP22 remains to be discovered, our results support the hypothesis that this protein serves multiple functions in Schwann cells.

Charcot-Marie-Tooth Disease↗
PubMed1996

Molecular approaches towards the isolation of tyrosine phosphatases expressed in the peripheral nervous system.

Protein tyrosine phosphatases (PTP) are increasingly appreciated to play a crucial function in the development, homeostasis and regeneration of the nervous system. In an attempt to determine the set of PTPs that are expressed in the PNS, we have employed polymerase chain reaction (PCR)-based strategies. Degenerate oligonucleotide primers which were designed based on PTP-consensus motifs were used on substrate cDNAs derived from sciatic nerves of either 3, 10 or 60 days-old rats as well as from cultured rat Schwann cells. The resulting partial PTP clones were used for low-stringency hybridization screening of a cDNA library constructed from the sciatic nerves of 7 to 8 days-old rats. The combined approaches yielded three known rat PTPs and at least three potential rat species homologues of previously identified mouse PTPs. Furthermore, several partial clones encoding potentially novel PTPs have been isolated. The suitability of our experimental approaches for the identification and characterization of PNS-expressed PTPs will be discussed.

Aging↗
PubMed1995

Widespread expression of the peripheral myelin protein-22 gene (PMP22) in neural and non-neural tissues during murine development.

The gene encoding the peripheral myelin protein PMP22 is affected by various mutations in the hereditary peripheral neuropathies Charcot-Marie-Tooth disease type 1A (CMT1A), Déjérine-Sottas syndrome (DSS) and hereditary neuropathy with liability to pressure palsies (HNPP). In contrast to the recent remarkable progress in the genetics of the PMP22 gene, the biological function of PMP22 remains largely unknown. In this report, we have confirmed by using in situ hybridization techniques that high levels of PMP22 mRNA are present in maturing peripheral nerves of the 2-week-old mouse, a finding consistent with the PNS-specific defect observed in hereditary peripheral neuropathies. However, high levels of PMP22 transcripts were also found in the villi of the adult gut, and PMP22 expression was detected in various non-neural tissues during embryonic mouse development. In early embryogenesis (9.5 days postconception, dpc), PMP22 RNA expression appears restricted to the epithelial ectodermal layer. During early organogenesis (11.5 dpc), particularly high levels of expression are present in the capsule surrounding the liver and in the forming gut, while low levels of PMP22 mRNA can be found in precartilagous condensations forming the vertebrae and the ventricular layer of the myelencephalon. During midgestation development (14.5 dpc to 16.5 dpc), the number of PMP22-positive tissues increases, and high expression is detected in several mesoderm-derived tissues, in particular connective tissues of the face region, bones including the vertebrae, the lung mesenchym, and in muscles. In addition, high expression is also found in ectoderm-derived tissues, especially the epithelia of the lens and the skin. These findings strongly suggest that PMP22 serves not only a PNS-specific function but is also of broader biological significance in cell proliferation and/or differentiation.

Age Factors↗
PubMed1995

Epithelial membrane protein-1, peripheral myelin protein 22, and lens membrane protein 20 define a novel gene family.

Peripheral myelin protein 22 (PMP22) is expressed in many tissues but mainly by Schwann cells as a component of compact myelin of the peripheral nervous system (PNS). Mutations affecting PMP22 are associated with hereditary motor and sensory neuropathies. Although these phenotypes are restricted to the PNS, PMP22 is thought to play a dual role in myelin formation and in cell proliferation. We describe the cloning and characterization of epithelial membrane protein-1 (EMP-1), a putative four-transmembrane protein of 160 amino acids with 40% amino acid identity to PMP22. EMP-1 and PMP22 are co-expressed in most tissues but with differences in relative expression levels. EMP-1 is most prominently found in the gastrointestinal tract, skin, lung, and brain but not in liver. In the corpus gastricum, EMP-1 protein can be detected in epithelial cells of the gastric pit and isthmus of the gastric gland in a pattern consistent with plasma membrane association. EMP-1 and PMP22 mRNA levels are inversely regulated in the degenerating rat sciatic nerve after injury and by growth arrest in NIH 3T3 fibroblasts. The discovery of EMP-1 as the second member of a novel gene family led to the identification of the lens-specific membrane protein 20 (MP20) as a third but distant relative. The proteins of this family are likely to serve similar functions possibly related to cell proliferation and differentiation in a variety of cell types.

3T3 Cells↗
PubMed1995

Peripheral myelin protein 22: facts and hypotheses.

Mutations affecting the peripheral myelin protein 22 (PMP22) gene are associated with inherited motor and sensory neuropathies in mouse (Trembler and Trembler-J) and human (Charcot-Marie-Tooth disease type 1A and Dejerine-Sottas syndrome). Although genetic studies have established a critical role of PMP22 in the formation and/or maintenance of myelin in the peripheral nervous system, the biological function of PMP22 in myelin and in non-myelin forming cells remains largely enigmatic. In this Mini-Review, we will summarize the current knowledge about PMP22 and discuss its hypothetical function(s) in a broad context.

Animals↗
PubMed1995

Hypermyelination and demyelinating peripheral neuropathy in Pmp22-deficient mice.

Peripheral myelin protein PMP22 has been suggested to have a role in peripheral nerve myelination and cell proliferation. Defects at the PMP22 locus are associated with peripheral neuropathies such as Charcot-Marie-Tooth disease type 1A. We now demonstrate that mice devoid of Pmp22 are retarded in the onset of myelination and develop abundant sausage-like hypermyelination structures (tomacula) at a young age followed by severe demyelination, axonal loss and functional impairment. Mice carrying one functional copy of Pmp22 are less affected but they also exhibit focal tomacula comparable to the morphological features in hereditary neuropathy with liability to pressure palsies (HNPP). We conclude that Pmp22 is required for the correct development of peripheral nerves, the maintenance of axons and the determination of myelin thickness and stability.

Animals↗
PubMed1995

Molecular basis of common hereditary motor and sensory neuropathies in humans and in mouse models.

The Hereditary Motor and Sensory Neuropathies (HMSNs) are well known to be clinically, morphologically, and genetically heterogeneous. Yet, recent advances in the cellular and molecular biology of the peripheral nervous system coupled with remarkable progress in human and mouse genetics have provided a framework that has profoundly changed our understanding of the pathogenesis of these diseases. It now appears that most of the HMSNs are related to mutations affecting genes encoding Schwann cell proteins, specifically the Peripheral Myelin Protein PMP22, Myelin Protein Zero, and one of the gap junction proteins, connexin-32. Accordingly, these findings are discussed in the context of the clinical and pathologic features of the human HMSNs, but are interpreted in the context of basic research findings on the cellular and molecular biology of the peripheral nervous system derived from in vivo and in vitro studies in spontaneously-occurring and genetically engineered animal models for the HMSNs.

Animals↗
PubMed1995

Molecular anatomy and genetics of myelin proteins in the peripheral nervous system.

Myelin contains a number of proteins, the major examples of which are protein zero (Po), P2 protein, peripheral myelin protein 22 (PMP22), myelin basic proteins (MBPs), myelin-associated glycoprotein (MAG) and the recently described connexin 32 (Cx32). This list is probably still incomplete. The localisation and possible functions of these proteins are reviewed. In the past few years a number of inherited demyelinating neuropathies in mice and the human have been shown to be due to mutations affecting the genes PMP22, Po and Cx32 so that it has become possible to characterise the molecular pathology of the majority of these disorders. This has provided important insights into the relationships between the structure of myelin and the function of its constituent proteins.

Animals↗
PubMed1994

Regulation of tissue-specific expression of alternative peripheral myelin protein-22 (PMP22) gene transcripts by two promoters.

Mutations affecting the peripheral myelin protein-22 (PMP22) gene have been shown to be associated with inherited peripheral neuropathies. To provide the molecular basis for the analysis of such mutations, we have cloned and characterized the human PMP22 gene. It spans approximately 40 kilobases and contains four coding exons. Detailed analysis of its 5'-flanking region suggested the presence of two alternatively transcribed, but untranslated exons. Mapping of separate PMP22 mRNA transcription initiation sites to each of these exons indicates that PMP22 expression is regulated by two alternatively used promoters. In support of this hypothesis, both putative promoter sequences demonstrated the ability to drive expression of reporter genes in transfection experiments. Furthermore, the structures of the 5'-portions of the PMP22 genes appear to be identical in rat and human, supporting the biological significance of the observed arrangement of regulatory regions. The relative expression of the alternative PMP22 transcripts is tissue-specific, and high levels of the exon 1A-containing transcript are tightly coupled to myelin formation. In contrast, exon 1B-containing transcripts are predominant in non-neural tissues and in growth-arrested primary fibroblasts. Interestingly, although a strong upregulation of PMP22 mRNA was observed in cultured Schwann cells in the presence of the adenylate cyclase activator forskolin under various culture conditions, the regulation of the different PMP22 mRNA species did not mimic the regulation that occurs during myelin formation in vivo. The observed regulation of the PMP22 gene by a complex molecular mechanism is consistent with the proposed dual role of PMP22 in neural and non-neural tissue.

Alternative Splicing↗
PubMed1994

Genetic basis of inherited peripheral neuropathies.

Progress in the elucidation of the genetic basis for inherited peripheral neuropathies has been remarkable over the last years. In particular, the molecular mechanisms underlying the autosomal dominantly inherited disorders Charcot-Marie-Tooth disease type 1A (CMT1A), Charcot-Marie-Tooth disease type 1B (CMT1B), and hereditary neuropathy with liability to pressure palsies (HNPP) have been determined. While mutation in the gene encoding the major myelin protein, P0 has been associated with CMT1B, CMT1A and HNPP have been shown to be associated with reciprocal recombination events leading either to a large submicroscopic duplication in CMT1A, or the corresponding DNA deletion in HNPP. Available evidence is consistent with the hypothesis that one or more genes within the relevant rearranged segment of 1.5 Mb on chromosome 17 is sensitive to gene dosage providing a novel mechanism for inherited human disorders. It is likely that the gene encoding the peripheral myelin protein PMP22 is at least one of the genes involved since the PMP22 gene maps within the CMT1A duplication (or HNPP deletion), and point mutations within it have been shown to cause a CMT phenotype in humans and comparable neuropathies in rodents (trembler and tremblerJ). The mechanism(s) by which gene dosage and point mutations affecting the same gene might lead to a similar phenotype are currently unknown but recent transgenic mouse experiments suggest that similar mechanisms may also underlie other genetic diseases.

Animals↗
PubMed1993

The carboxyl terminus of nerve growth factor is required for biological activity.

A series of mouse nerve growth factor (NGF) deletion mutants have been constructed using in vitro mutagenesis to define domains of the protein essential for its activity. Deletions of the amino or carboxyl termini of mature NGF or of an internal domain, which normally produces a surface-exposed reverse turn, have been analyzed. Mutants with deletions in the amino terminus or in the reverse turn retain significant biological activity, whereas, in contrast, a mutant NGF lacking the seven most carboxyl-terminal amino acids is appropriately synthesized but shows no measurable biological activity. These results suggests that the flexible carboxyl tail of NGF, and perhaps other neurotrophins, plays a crucial role in mediating receptor recognition and/or ligand binding.

Animals↗
PubMed1993

Charcot-Marie-Tooth disease type 1A. Association with a spontaneous point mutation in the PMP22 gene.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. CMT type 1A is associated with a 1.5-megabase DNA duplication in region p11.2-p12 of chromosome 17 in most patients. An increased dosage of a gene within the duplicated segment appears to cause the disease. The PMP22 gene, which encodes a myelin protein, has been mapped within the duplication and proposed as a candidate gene for CMT type 1A. METHODS: We analyzed DNA samples from a cohort of 32 unrelated patients with CMT type 1 who did not have the 1.5-Mb tandem duplication in 17p11.2-p12 for mutations within the PMP22 coding region. Molecular techniques included the polymerase chain reaction (PCR), heteroduplex analysis to detect point mutations, and direct nucleotide-sequence determination of amplified PCR products. RESULTS: A 10-year-old boy was identified with a point mutation in PMP22, which resulted in the substitution of cysteine for serine in a putative transmembrane domain of PMP22. Analysis of family members revealed that the PMP22 point mutation arose spontaneously and segregated with the CMT type 1 phenotype in an autosomal dominant pattern. The patients with the PMP22 point mutation had clinical and electrophysiologic phenotypes that were similar to those of patients with the 1.5-Mb duplication. CONCLUSIONS: The PMP22 gene has a causative role in CMT type 1. Either a point mutation in PMP22 or a duplication of the region including the PMP22 gene can result in the disease phenotype.

Amino Acid Sequence↗
PubMed1993

Detection and processing of peripheral myelin protein PMP22 in cultured Schwann cells.

Peripheral myelin protein, 22 kDa (PMP22), is a myelin molecule associated with Schwann cells in peripheral nerves (Snipes, G. J., Suter, U., Welcher, A. A., and Shooter, E. M. (1992) J. Cell Biol. 117, 225-238). Mutations affecting the PMP22 gene have been implicated in the trembler mutation in mice (Suter, U., Welcher, A. A., Ozcelik, T., Snipes, G. J., Kosaras, B., Francke, U., Billings-Gagliardi, S., Sidman, R. L., and Shooter, E. M. (1992) Nature 356, 241-244; Suter, U., Moskow, J. J., Welcher, A. A., Snipes, G. J., Kosaras, B., Sidman, R. L., Buchberg, A. M., and Shooter, E. M. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 4382-4386) and Charcot-Marie-Tooth Disease in humans (Patel, P. I., Roa, B. B., Welcher, A. A., Schoener-Scott, R., Trask, B. J., Pentao, L., Snipes, G. J., Garcia, C. A., Francke, U., Shooter, E. M., Lupski, J. R., and Suter, U. (1992) Nature genet. 1, 159-165). In this report, we have studied PMP22 production in cultured rat Schwann cells. Schwann cells contain a 1.8-kilobase mRNA transcript coding for PMP22, and its production is up-regulated in vitro by forskolin. Metabolic labeling combined with immunoprecipitation methods using antibodies raised against synthetic peptides of PMP22 reveal that Schwann cells generate the protein from an 18-kDa precursor form which is post-translationally modified by N-linked glycosylation. A second molecule (molecular mass, 48 kDa) that reacted with PMP22 antibodies was also detected in Schwann cells but is not related chemically to PMP22 as determined by pulse-chase labeling. Metabolic labeling of rat sciatic nerve and Western blot analyses of purified rat sciatic nerve myelin reveal that deglycosylation of PMP22 gives rise to an 18-kDa protein similar in size to that in Schwann cells. These results indicate that cultured Schwann cells may provide a good model in which to investigate the production and function of PMP22 and to establish the cellular basis for the protein's involvement in inherited peripheral neuropathies.

Amino Acid Sequence↗