The Experts below are selected from a list of 759 Experts worldwide ranked by ideXlab platform
Claude Cassagne - One of the best experts on this subject based on the ideXlab platform.
-
sphingolipid metabolic disorders in Trembler mouse peripheral nerves in vivo result from an abnormal substrate supply
Journal of Neurochemistry, 2002Co-Authors: Anthony M. Heape, Bertrand Garbay, Francoise Boironsargueil, Jeanjacques Bessoule, Claude CassagneAbstract:Sphingolipid metabolic pathways in the peripheral nerves of dysmyelinating Trembler mice were studied in vivo, using intraneurally injected [3H]palmitate as the exogenous substrate. The kinetic analysis of the experimental data obtained for the mutant revealed that, as in normal nerves, two metabolically and kinetically independent pathways are implicated in the biosynthesis of the major peripheral nerve sphingolipids: the ceramide pathway and another pathway in which there is no detectable labeled intermediate ("direct amidification"). The results also show that, in the Trembler mouse sciatic nerves: (a) The severely deficient sphingolipid biosynthesis results from the constitution of a qualitatively and quantitatively abnormal fatty acid substrate pool destined for metabolism via the ceramide pathway, which ensures the totality of the galactocerebroside labeling and two-thirds of that of sphingomyelin. The ceramide intermediates of this pathway are labeled only on their fatty acyl moiety, which contains only 16-carbon atom chains. (b) "Direct amidification" events implicated in sphingolipid labeling are decreased compared with normal and account for the remaining sphingomyelin formation.
-
Zinc finger proteins in the peripheral nerve of adult normal and Trembler mice.
Journal of The Peripheral Nervous System, 2001Co-Authors: Isabelle Labatut-cazabat, Bertrand Garbay, Claude Cassagne, Alexandre Faveraux, Souad Hilmi, Claude Vital, Klaus G. PetryAbstract:By using monoclonal antibodies directed against the conserved zinc binding site of zinc finger proteins, we detected 2 prominent zinc finger proteins in rat peripheral nervous system (PNS) during development, and in adult normal and Trembler mice sciatic nerves. The protein of 55 kDa is abundant in adult normal mice and rats, but is weakly expressed in adult Trembler mice. The 29 kDa protein is expressed in neonatal rats and in the Trembler mouse, but is absent in adult rats and mice. These results suggest that the Schwann cell proliferation stage may be associated with the 29 kDa protein expression, and the 55 kDa protein may be implicated in the PNS myelination process.
-
Trembler as a mouse model of cmt1a
Annals of the New York Academy of Sciences, 1999Co-Authors: Bertrand Garbay, Anthony M. Heape, Jacques Bonnet, Jerome Salles, Anja Knoll, Francoise Boironsargueil, Claude CassagneAbstract:The Trembler mouse suffers from a dominantly inherited autosomal mutation that results in an abnormal myelination of the peripheral nervous system. Biochemical studies have shown that dysmyelination is the primary event, demyelination being a late-occurring process. The expression of myelin protein genes has been studied. The steady-state levels for PMP22 mRNA represent 10 and 5% of normal values in the nerves of heterozygous and homozygous Trembler, respectively. This is due to a reduced expression of the specific transcript driven by the promoter 1 of the PMP22 gene. Collective results indicate that Trembler dysmyelination is not necessarily the consequence of a large accumulation of the mutated PMP22 protein. Moreover, it appears that the situation in the Trembler is different from that encountered in most CMT1A patients, where an increased PMP22 gene dosage is responsible for the disease. Therefore, the Trembler mutant is perhaps not an ideal model for this human neuropathy.
-
high metabolism and subsequent elongation of 3 hydroxyeicosanoyl coa in very long chain fatty acid deficient pns of Trembler mice
Neuroscience Letters, 1999Co-Authors: Francoise Sargueil, Bertrand Garbay, Jerome Salles, Anja Knoll, Claude CassagneAbstract:The developmental patterns of the overall fatty acid elongation and of the last two partial activities of microsomal elongase (dehydration and reduction of 3-hydroxyacyl-CoA) were investigated in the PNS of normal and Trembler mice. Unexpectedly, Trembler microsomes synthesized normal C22-CoA amounts from 3-hydroxyeicosanoyl-CoA (3-OHC20-CoA), a C18-CoA elongation intermediate. Hydroxy- acyl-CoA dehydrase and enoyl-CoA reductase activities were found to be higher in the mutant than in the control, whatever the stage of development. Moreover, C20-CoA elongation led to normal C22-CoA and C24-CoA formation in the mutant whereas C20-CoA formation from C18-CoA was always far lower in Trembler than in control. C18-CoA condensing enzyme emerges as the only elongation step involved in the VLCFA deficit evidenced in Trembler PNS.
-
pathways of incorporation of fatty acid into glycerolipids of the murine peripheral nervous system in vivo alterations in the dysmyelinating mutant Trembler mouse
Neurochemistry International, 1996Co-Authors: Anthony M. Heape, Francoise Boironsargueil, Jeanjacques Bessoule, Claude CassagneAbstract:Abstract In vivo glycerolipid metabolism was studied in sciatic nerves of normal and Trembler mice. The results showed that two kinetically independent pathways were implicated in the labeling of diacylglycerophospholipids from [3H]palmitate: the Kennedy pathway and a ‘direct acylation’ pathway. In normal nerves, 45% of the glycerophospholipids were labeled, with a rate constant k3 = 3.9 × 10−3 min−1, from phosphatidic acid and diacylglycerol intermediates, themselves formed with a rate constant of k1 = 0.24 min−1 from a free 3H-fatty acid pool, FFA1, that represents 45% of the total injected label. The remaining 55% of the glycerophospholipids were labeled from a kinetically distinct free 3H-fatty acid pool, FFA2, with a rate constant of k4 = 9.8 × 10−2, via a process that does not implicate a detectably labeled metabolic intermediate (‘direct acylation’). Glycerophospholipid labeling via the Kennedy pathway in the Trembler mouse sciatic nerves was reduced to 75% of the normal level, while labeling via the ‘direct acylation’ pathway was increased 1.4-fold. The values of the rate constants for free 3H-fatty acid utilisation (k1 and k4) were both increased about 2.5-fold, while that of glycerophospholipid formation from diacylglycerol (k3) was close to normal. Copyright © 1996 Elsevier Science Ltd
Bertrand Garbay - One of the best experts on this subject based on the ideXlab platform.
-
sphingolipid metabolic disorders in Trembler mouse peripheral nerves in vivo result from an abnormal substrate supply
Journal of Neurochemistry, 2002Co-Authors: Anthony M. Heape, Bertrand Garbay, Francoise Boironsargueil, Jeanjacques Bessoule, Claude CassagneAbstract:Sphingolipid metabolic pathways in the peripheral nerves of dysmyelinating Trembler mice were studied in vivo, using intraneurally injected [3H]palmitate as the exogenous substrate. The kinetic analysis of the experimental data obtained for the mutant revealed that, as in normal nerves, two metabolically and kinetically independent pathways are implicated in the biosynthesis of the major peripheral nerve sphingolipids: the ceramide pathway and another pathway in which there is no detectable labeled intermediate ("direct amidification"). The results also show that, in the Trembler mouse sciatic nerves: (a) The severely deficient sphingolipid biosynthesis results from the constitution of a qualitatively and quantitatively abnormal fatty acid substrate pool destined for metabolism via the ceramide pathway, which ensures the totality of the galactocerebroside labeling and two-thirds of that of sphingomyelin. The ceramide intermediates of this pathway are labeled only on their fatty acyl moiety, which contains only 16-carbon atom chains. (b) "Direct amidification" events implicated in sphingolipid labeling are decreased compared with normal and account for the remaining sphingomyelin formation.
-
Zinc finger proteins in the peripheral nerve of adult normal and Trembler mice.
Journal of The Peripheral Nervous System, 2001Co-Authors: Isabelle Labatut-cazabat, Bertrand Garbay, Claude Cassagne, Alexandre Faveraux, Souad Hilmi, Claude Vital, Klaus G. PetryAbstract:By using monoclonal antibodies directed against the conserved zinc binding site of zinc finger proteins, we detected 2 prominent zinc finger proteins in rat peripheral nervous system (PNS) during development, and in adult normal and Trembler mice sciatic nerves. The protein of 55 kDa is abundant in adult normal mice and rats, but is weakly expressed in adult Trembler mice. The 29 kDa protein is expressed in neonatal rats and in the Trembler mouse, but is absent in adult rats and mice. These results suggest that the Schwann cell proliferation stage may be associated with the 29 kDa protein expression, and the 55 kDa protein may be implicated in the PNS myelination process.
-
Trembler as a mouse model of cmt1a
Annals of the New York Academy of Sciences, 1999Co-Authors: Bertrand Garbay, Anthony M. Heape, Jacques Bonnet, Jerome Salles, Anja Knoll, Francoise Boironsargueil, Claude CassagneAbstract:The Trembler mouse suffers from a dominantly inherited autosomal mutation that results in an abnormal myelination of the peripheral nervous system. Biochemical studies have shown that dysmyelination is the primary event, demyelination being a late-occurring process. The expression of myelin protein genes has been studied. The steady-state levels for PMP22 mRNA represent 10 and 5% of normal values in the nerves of heterozygous and homozygous Trembler, respectively. This is due to a reduced expression of the specific transcript driven by the promoter 1 of the PMP22 gene. Collective results indicate that Trembler dysmyelination is not necessarily the consequence of a large accumulation of the mutated PMP22 protein. Moreover, it appears that the situation in the Trembler is different from that encountered in most CMT1A patients, where an increased PMP22 gene dosage is responsible for the disease. Therefore, the Trembler mutant is perhaps not an ideal model for this human neuropathy.
-
high metabolism and subsequent elongation of 3 hydroxyeicosanoyl coa in very long chain fatty acid deficient pns of Trembler mice
Neuroscience Letters, 1999Co-Authors: Francoise Sargueil, Bertrand Garbay, Jerome Salles, Anja Knoll, Claude CassagneAbstract:The developmental patterns of the overall fatty acid elongation and of the last two partial activities of microsomal elongase (dehydration and reduction of 3-hydroxyacyl-CoA) were investigated in the PNS of normal and Trembler mice. Unexpectedly, Trembler microsomes synthesized normal C22-CoA amounts from 3-hydroxyeicosanoyl-CoA (3-OHC20-CoA), a C18-CoA elongation intermediate. Hydroxy- acyl-CoA dehydrase and enoyl-CoA reductase activities were found to be higher in the mutant than in the control, whatever the stage of development. Moreover, C20-CoA elongation led to normal C22-CoA and C24-CoA formation in the mutant whereas C20-CoA formation from C18-CoA was always far lower in Trembler than in control. C18-CoA condensing enzyme emerges as the only elongation step involved in the VLCFA deficit evidenced in Trembler PNS.
-
expression of the exon 1a containing pmp22 transcript is altered in the Trembler mouse
Neuroscience Letters, 1995Co-Authors: Bertrand Garbay, Francoise Boironsargueil, Claude CassagneAbstract:The Trembler mouse suffers from a dominantly inherited mutation of the peripheral myelin protein 22 (PMP22) gene which results in an abnormal myelination of its peripheral nervous system. The recent identification of two different PMP22 mRNA differing in their 5' non-translated region led us to monitor their respective levels of expression in the Trembler peripheral nervous system (PNS) during the myelination period. We showed that the steady-state levels of the exon 1A-containing transcript, which is thought to be involved in the myelination process, were greatly reduced in heterozygous and homozygous Trembler mice when compared to the normal animals. Such a difference was not observed for the exon 1B-containing transcript. Therefore, our results support the idea that the two alternatively used promoters of the PMP22 gene are under different regulation control, and that the up-regulation of the exon 1A-transcript is necessary for the normal myelination of the mouse PNS.
Anthony M. Heape - One of the best experts on this subject based on the ideXlab platform.
-
sphingolipid metabolic disorders in Trembler mouse peripheral nerves in vivo result from an abnormal substrate supply
Journal of Neurochemistry, 2002Co-Authors: Anthony M. Heape, Bertrand Garbay, Francoise Boironsargueil, Jeanjacques Bessoule, Claude CassagneAbstract:Sphingolipid metabolic pathways in the peripheral nerves of dysmyelinating Trembler mice were studied in vivo, using intraneurally injected [3H]palmitate as the exogenous substrate. The kinetic analysis of the experimental data obtained for the mutant revealed that, as in normal nerves, two metabolically and kinetically independent pathways are implicated in the biosynthesis of the major peripheral nerve sphingolipids: the ceramide pathway and another pathway in which there is no detectable labeled intermediate ("direct amidification"). The results also show that, in the Trembler mouse sciatic nerves: (a) The severely deficient sphingolipid biosynthesis results from the constitution of a qualitatively and quantitatively abnormal fatty acid substrate pool destined for metabolism via the ceramide pathway, which ensures the totality of the galactocerebroside labeling and two-thirds of that of sphingomyelin. The ceramide intermediates of this pathway are labeled only on their fatty acyl moiety, which contains only 16-carbon atom chains. (b) "Direct amidification" events implicated in sphingolipid labeling are decreased compared with normal and account for the remaining sphingomyelin formation.
-
Trembler as a mouse model of cmt1a
Annals of the New York Academy of Sciences, 1999Co-Authors: Bertrand Garbay, Anthony M. Heape, Jacques Bonnet, Jerome Salles, Anja Knoll, Francoise Boironsargueil, Claude CassagneAbstract:The Trembler mouse suffers from a dominantly inherited autosomal mutation that results in an abnormal myelination of the peripheral nervous system. Biochemical studies have shown that dysmyelination is the primary event, demyelination being a late-occurring process. The expression of myelin protein genes has been studied. The steady-state levels for PMP22 mRNA represent 10 and 5% of normal values in the nerves of heterozygous and homozygous Trembler, respectively. This is due to a reduced expression of the specific transcript driven by the promoter 1 of the PMP22 gene. Collective results indicate that Trembler dysmyelination is not necessarily the consequence of a large accumulation of the mutated PMP22 protein. Moreover, it appears that the situation in the Trembler is different from that encountered in most CMT1A patients, where an increased PMP22 gene dosage is responsible for the disease. Therefore, the Trembler mutant is perhaps not an ideal model for this human neuropathy.
-
pathways of incorporation of fatty acid into glycerolipids of the murine peripheral nervous system in vivo alterations in the dysmyelinating mutant Trembler mouse
Neurochemistry International, 1996Co-Authors: Anthony M. Heape, Francoise Boironsargueil, Jeanjacques Bessoule, Claude CassagneAbstract:Abstract In vivo glycerolipid metabolism was studied in sciatic nerves of normal and Trembler mice. The results showed that two kinetically independent pathways were implicated in the labeling of diacylglycerophospholipids from [3H]palmitate: the Kennedy pathway and a ‘direct acylation’ pathway. In normal nerves, 45% of the glycerophospholipids were labeled, with a rate constant k3 = 3.9 × 10−3 min−1, from phosphatidic acid and diacylglycerol intermediates, themselves formed with a rate constant of k1 = 0.24 min−1 from a free 3H-fatty acid pool, FFA1, that represents 45% of the total injected label. The remaining 55% of the glycerophospholipids were labeled from a kinetically distinct free 3H-fatty acid pool, FFA2, with a rate constant of k4 = 9.8 × 10−2, via a process that does not implicate a detectably labeled metabolic intermediate (‘direct acylation’). Glycerophospholipid labeling via the Kennedy pathway in the Trembler mouse sciatic nerves was reduced to 75% of the normal level, while labeling via the ‘direct acylation’ pathway was increased 1.4-fold. The values of the rate constants for free 3H-fatty acid utilisation (k1 and k4) were both increased about 2.5-fold, while that of glycerophospholipid formation from diacylglycerol (k3) was close to normal. Copyright © 1996 Elsevier Science Ltd
-
Cerebroside formation in the peripheral nervous system of normal and Trembler mice
Neuroscience letters, 1995Co-Authors: Françoise Boiron-sargueil, Anthony M. Heape, Bertrand Garbay, Claude CassagneAbstract:Abstract The formation of cerebrosides by the galactosylation of ceramides was investigated in a microsomal fraction prepared from sciatic nerves of normal and Trembler mice. In the control, cerebroside synthesis is observed in the presence of uridine-diphosphate-galactose both from endogenously synthesized [1- 14 C]stearoyl-sphingosine (C18-ceramide), and from [1- 14 C]lignoceroyl-sphingosine (C24ceramide). Cerebroside formation is also demonstrated by studying the galactosylation of exogenous ceramides with UDP[1- 14 C]-galactose. In the mutant, only trace amounts of labeled cerebrosides are formed from labeled stearoyl-sphingosine, whereas with lignoceroyl-sphingosine, no cerebroside synthesis is detected under conditions allowing their formation in the control. However, a higher rate of synthesis of short acyl chain-glucosyl ceramides is observed in the Trembler samples.
Francoise Boironsargueil - One of the best experts on this subject based on the ideXlab platform.
-
sphingolipid metabolic disorders in Trembler mouse peripheral nerves in vivo result from an abnormal substrate supply
Journal of Neurochemistry, 2002Co-Authors: Anthony M. Heape, Bertrand Garbay, Francoise Boironsargueil, Jeanjacques Bessoule, Claude CassagneAbstract:Sphingolipid metabolic pathways in the peripheral nerves of dysmyelinating Trembler mice were studied in vivo, using intraneurally injected [3H]palmitate as the exogenous substrate. The kinetic analysis of the experimental data obtained for the mutant revealed that, as in normal nerves, two metabolically and kinetically independent pathways are implicated in the biosynthesis of the major peripheral nerve sphingolipids: the ceramide pathway and another pathway in which there is no detectable labeled intermediate ("direct amidification"). The results also show that, in the Trembler mouse sciatic nerves: (a) The severely deficient sphingolipid biosynthesis results from the constitution of a qualitatively and quantitatively abnormal fatty acid substrate pool destined for metabolism via the ceramide pathway, which ensures the totality of the galactocerebroside labeling and two-thirds of that of sphingomyelin. The ceramide intermediates of this pathway are labeled only on their fatty acyl moiety, which contains only 16-carbon atom chains. (b) "Direct amidification" events implicated in sphingolipid labeling are decreased compared with normal and account for the remaining sphingomyelin formation.
-
Trembler as a mouse model of cmt1a
Annals of the New York Academy of Sciences, 1999Co-Authors: Bertrand Garbay, Anthony M. Heape, Jacques Bonnet, Jerome Salles, Anja Knoll, Francoise Boironsargueil, Claude CassagneAbstract:The Trembler mouse suffers from a dominantly inherited autosomal mutation that results in an abnormal myelination of the peripheral nervous system. Biochemical studies have shown that dysmyelination is the primary event, demyelination being a late-occurring process. The expression of myelin protein genes has been studied. The steady-state levels for PMP22 mRNA represent 10 and 5% of normal values in the nerves of heterozygous and homozygous Trembler, respectively. This is due to a reduced expression of the specific transcript driven by the promoter 1 of the PMP22 gene. Collective results indicate that Trembler dysmyelination is not necessarily the consequence of a large accumulation of the mutated PMP22 protein. Moreover, it appears that the situation in the Trembler is different from that encountered in most CMT1A patients, where an increased PMP22 gene dosage is responsible for the disease. Therefore, the Trembler mutant is perhaps not an ideal model for this human neuropathy.
-
pathways of incorporation of fatty acid into glycerolipids of the murine peripheral nervous system in vivo alterations in the dysmyelinating mutant Trembler mouse
Neurochemistry International, 1996Co-Authors: Anthony M. Heape, Francoise Boironsargueil, Jeanjacques Bessoule, Claude CassagneAbstract:Abstract In vivo glycerolipid metabolism was studied in sciatic nerves of normal and Trembler mice. The results showed that two kinetically independent pathways were implicated in the labeling of diacylglycerophospholipids from [3H]palmitate: the Kennedy pathway and a ‘direct acylation’ pathway. In normal nerves, 45% of the glycerophospholipids were labeled, with a rate constant k3 = 3.9 × 10−3 min−1, from phosphatidic acid and diacylglycerol intermediates, themselves formed with a rate constant of k1 = 0.24 min−1 from a free 3H-fatty acid pool, FFA1, that represents 45% of the total injected label. The remaining 55% of the glycerophospholipids were labeled from a kinetically distinct free 3H-fatty acid pool, FFA2, with a rate constant of k4 = 9.8 × 10−2, via a process that does not implicate a detectably labeled metabolic intermediate (‘direct acylation’). Glycerophospholipid labeling via the Kennedy pathway in the Trembler mouse sciatic nerves was reduced to 75% of the normal level, while labeling via the ‘direct acylation’ pathway was increased 1.4-fold. The values of the rate constants for free 3H-fatty acid utilisation (k1 and k4) were both increased about 2.5-fold, while that of glycerophospholipid formation from diacylglycerol (k3) was close to normal. Copyright © 1996 Elsevier Science Ltd
-
expression of the exon 1a containing pmp22 transcript is altered in the Trembler mouse
Neuroscience Letters, 1995Co-Authors: Bertrand Garbay, Francoise Boironsargueil, Claude CassagneAbstract:The Trembler mouse suffers from a dominantly inherited mutation of the peripheral myelin protein 22 (PMP22) gene which results in an abnormal myelination of its peripheral nervous system. The recent identification of two different PMP22 mRNA differing in their 5' non-translated region led us to monitor their respective levels of expression in the Trembler peripheral nervous system (PNS) during the myelination period. We showed that the steady-state levels of the exon 1A-containing transcript, which is thought to be involved in the myelination process, were greatly reduced in heterozygous and homozygous Trembler mice when compared to the normal animals. Such a difference was not observed for the exon 1B-containing transcript. Therefore, our results support the idea that the two alternatively used promoters of the PMP22 gene are under different regulation control, and that the up-regulation of the exon 1A-transcript is necessary for the normal myelination of the mouse PNS.
Eric M. Shooter - One of the best experts on this subject based on the ideXlab platform.
-
differential aggregation of the Trembler and Trembler j mutants of peripheral myelin protein 22
Journal of The Peripheral Nervous System, 2002Co-Authors: Andreas R Tobler, Ning Liu, Lukas A Mueller, Eric M. ShooterAbstract:Mutations in the gene encoding the peripheral myelin protein 22 (PMP22), a tetraspan protein in compact peripheral myelin, are one of the causes of inherited demyelinating peripheral neuropathy. Most PMP22 mutations alter the trafficking of the PMP22 protein in Schwann cells, and this different trafficking has been proposed as the underlying mechanism of the disease. To explore this problem further, we compared the aggregation of wild-type Pmp22 with those of the two Pmp22 mutations found in Trembler (Tr) and Trembler J (TrJ) mice. All three Pmp22s can be crosslinked readily as homodimers in transfected cells. Wild-type Pmp22 also forms heterodimers with Tr and TrJ Pmp22, and these heterodimers traffic with their respective mutant Pmp22 homodimers. All three Pmp22s form complexes larger than dimers with Tr Pmp22 especially prone to aggregate into high molecular weight complexes. Despite the differences in aggregation of Tr and TO Pmp22, these two mutant Pmp22s sequester the same amount of wild-type Pmp22 in heterodimers and heterooligomers. Thus, the differences in the phenotypes of Tr and TrJ mice may depend more on the ability of the mutant protein to aggregate than on the dominant-negative effect of the mutant Pmp22 on wild-type Pmp22 trafficking.
-
a leucine to proline mutation in the putative first transmembrane domain of the 22 kda peripheral myelin protein in the Trembler j mouse
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Ueli Suter, G. J. Snipes, A A Welcher, J J Moskow, B Kosaras, Richard L Sidman, A M Buchberg, Eric M. ShooterAbstract:Peripheral myelin protein PMP-22 is a potential growth-regulating myelin protein that is expressed by Schwann cells and predominantly localized in compact peripheral myelin. A point mutation in the Pmp-22 gene of inbred Trembler (Tr) mice was identified and proposed to be responsible for the Tr phenotype, which is characterized by paralysis of the limbs as well as tremors and transient seizures. In support of this hypothesis, we now report the fine mapping of the Pmp-22 gene to the immediate vicinity of the Tr locus on mouse chromosome 11. Furthermore, we have found a second point mutation in the Pmp-22 gene of Trembler-J (TrJ) mice, which results in the substitution of a leucine residue by a proline residue in the putative first transmembrane region of the PMP-22 polypeptide. Tr and TrJ were previously mapped genetically as possible allelic mutations giving rise to similar, but not identical, phenotypes. This finding is consistent with the discovery of two different mutations in physicochemically similar domains of the PMP-22 protein. Our results strengthen the hypothesis that mutations in the Pmp-22 gene can lead to heterogeneous forms of peripheral neuropathies and offer clues toward possible explanations for the dominant inheritance of these disorders.
-
Trembler mouse carries a point mutation in a myelin gene
Nature, 1992Co-Authors: Ueli Suter, G. J. Snipes, A A Welcher, B Kosaras, Richard L Sidman, Tayfun Ozcelik, Uta Francke, Susan Billingsgagliardi, Eric M. ShooterAbstract:The autosomal dominant Trembler mutation (Tr), maps to mouse chromosome 11 (ref. 2) and manifests as a Schwann-cell defect characterized by severe hypomyelination and continuing Schwann-cell proliferation throughout life. Affected animals move clumsily and develop tremor and transient seizures at a young age. We have recently described a potentially growth-regulating myelin protein, peripheral myelin protein-22 (PMP-22; refs 7, 8), which is expressed by Schwann cells and found in peripheral myelin. We now report the assignment of the gene for PMP-22 to mouse chromosome 11. Cloning and sequencing of PMP-22 complementary DNAs from inbred Tr mice reveals a point mutation that substitutes an aspartic acid residue for a glycine in a putative membrane-associated domain of the PMP-22 protein. Our results identify the PMP-22 gene as a likely candidate for the mouse Trembler locus and will encourage the search for mutations in the corresponding human gene in pedigrees with hypertrophic neuropathies such as Charcot-Marie-Tooth and Dejerine-Sottas diseases (hereditary motor and sensory neuropathies I and III).
