Distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a Pmp22 point mutation
Point mutations affecting PMP22 can cause hereditary demyelinating and dysmyelinating peripheral neuropathies. In addition, duplication and deletion of PMP22 are associated with Charcot–Marie–Tooth disease Type 1A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsy (HNPP), respectivel...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2005-04-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996104002724 |
| _version_ | 1818673360198959104 |
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| author | Guya Giambonini-Brugnoli Johanna Buchstaller Lukas Sommer Ueli Suter Ned Mantei |
| author_facet | Guya Giambonini-Brugnoli Johanna Buchstaller Lukas Sommer Ueli Suter Ned Mantei |
| author_sort | Guya Giambonini-Brugnoli |
| collection | DOAJ |
| description | Point mutations affecting PMP22 can cause hereditary demyelinating and dysmyelinating peripheral neuropathies. In addition, duplication and deletion of PMP22 are associated with Charcot–Marie–Tooth disease Type 1A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsy (HNPP), respectively. This study was designed to elucidate disease processes caused by misexpression of Pmp22 and, at the same time, to gain further information on the controversial molecular function of PMP22. To this end, we took advantage of the unique resource of a set of various Pmp22 mutant mice to carry out comparative expression profiling of mutant and wild-type sciatic nerves. Tissues derived from Pmp22−/− (“knockout”), Pmp22tg (increased Pmp22 copy number), and Trembler (Tr; point mutation in Pmp22) mutant mice were analyzed at two developmental stages: (i) at postnatal day (P)4, when normal myelination has just started and primary causative defects of the mutations are expected to be apparent, and (ii) at P60, with the goal of obtaining information on secondary disease effects. Interestingly, the three Pmp22 mutants exhibited distinct profiles of gene expression, suggesting different disease mechanisms. Increased expression of genes involved in cell cycle regulation and DNA replication is characteristic and specific for the early stage in Pmp22−/− mice, supporting a primary function of PMP22 in the regulation of Schwann cell proliferation. In the Tr mutant, a distinguishing feature is the high expression of stress response genes. Both Tr and Pmp22tg mice show strongly reduced expression of genes important for cholesterol synthesis at P4, a characteristic that is common to all three mutants at P60. Finally, we have identified a number of candidate genes that may play important roles in the disease process or in myelination per se. |
| first_indexed | 2024-12-17T07:54:33Z |
| format | Article |
| id | doaj.art-597398d24f864d579360615941f8f320 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T07:54:33Z |
| publishDate | 2005-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-597398d24f864d579360615941f8f3202022-12-21T21:57:45ZengElsevierNeurobiology of Disease1095-953X2005-04-01183656668Distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a Pmp22 point mutationGuya Giambonini-Brugnoli0Johanna Buchstaller1Lukas Sommer2Ueli Suter3Ned Mantei4Institute for Cell Biology, Department of Biology, ETH-Hönggerberg, Swiss Federal Institute of Technology, Schafmattstrasse 18, CH-8093 Zürich, SwitzerlandInstitute for Cell Biology, Department of Biology, ETH-Hönggerberg, Swiss Federal Institute of Technology, Schafmattstrasse 18, CH-8093 Zürich, SwitzerlandInstitute for Cell Biology, Department of Biology, ETH-Hönggerberg, Swiss Federal Institute of Technology, Schafmattstrasse 18, CH-8093 Zürich, SwitzerlandInstitute for Cell Biology, Department of Biology, ETH-Hönggerberg, Swiss Federal Institute of Technology, Schafmattstrasse 18, CH-8093 Zürich, SwitzerlandCorresponding author. Fax: +41 1 633 1069.; Institute for Cell Biology, Department of Biology, ETH-Hönggerberg, Swiss Federal Institute of Technology, Schafmattstrasse 18, CH-8093 Zürich, SwitzerlandPoint mutations affecting PMP22 can cause hereditary demyelinating and dysmyelinating peripheral neuropathies. In addition, duplication and deletion of PMP22 are associated with Charcot–Marie–Tooth disease Type 1A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsy (HNPP), respectively. This study was designed to elucidate disease processes caused by misexpression of Pmp22 and, at the same time, to gain further information on the controversial molecular function of PMP22. To this end, we took advantage of the unique resource of a set of various Pmp22 mutant mice to carry out comparative expression profiling of mutant and wild-type sciatic nerves. Tissues derived from Pmp22−/− (“knockout”), Pmp22tg (increased Pmp22 copy number), and Trembler (Tr; point mutation in Pmp22) mutant mice were analyzed at two developmental stages: (i) at postnatal day (P)4, when normal myelination has just started and primary causative defects of the mutations are expected to be apparent, and (ii) at P60, with the goal of obtaining information on secondary disease effects. Interestingly, the three Pmp22 mutants exhibited distinct profiles of gene expression, suggesting different disease mechanisms. Increased expression of genes involved in cell cycle regulation and DNA replication is characteristic and specific for the early stage in Pmp22−/− mice, supporting a primary function of PMP22 in the regulation of Schwann cell proliferation. In the Tr mutant, a distinguishing feature is the high expression of stress response genes. Both Tr and Pmp22tg mice show strongly reduced expression of genes important for cholesterol synthesis at P4, a characteristic that is common to all three mutants at P60. Finally, we have identified a number of candidate genes that may play important roles in the disease process or in myelination per se.http://www.sciencedirect.com/science/article/pii/S0969996104002724Pmp22MyelinTremblerMicroarraysE2FHeat shock proteins 1A and 1B |
| spellingShingle | Guya Giambonini-Brugnoli Johanna Buchstaller Lukas Sommer Ueli Suter Ned Mantei Distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a Pmp22 point mutation Neurobiology of Disease Pmp22 Myelin Trembler Microarrays E2F Heat shock proteins 1A and 1B |
| title | Distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a Pmp22 point mutation |
| title_full | Distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a Pmp22 point mutation |
| title_fullStr | Distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a Pmp22 point mutation |
| title_full_unstemmed | Distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a Pmp22 point mutation |
| title_short | Distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a Pmp22 point mutation |
| title_sort | distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a pmp22 point mutation |
| topic | Pmp22 Myelin Trembler Microarrays E2F Heat shock proteins 1A and 1B |
| url | http://www.sciencedirect.com/science/article/pii/S0969996104002724 |
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