Peripheral Myelin Protein 22 mRNA Research Articles

Expression of the exon 1A-containing PMP22 transcript is altered in the trembler mouse

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.

Chapter 32 The molecular basis of the neuropathies of mouse and human

Publisher Summary This chapter discusses the discovery of a gene for peripheral myelin protein 22 (PMP22) and its involvement in trembler neurological mutants. The cDNA for PMP22 was found in three independent library screens, two comparing the cDNAs from libraries made from normal rat sciatic nerve and from sciatic nerve after injury and the other comparing the cDNAs of quiescent and proliferating fibroblasts. In the latter instance, the gene was referred to as the growth arrest specific gene-3 because of its potential involvement in controlling growth in these cells. The cDNA encodes a small, extremely hydrophobic protein of 160 amino acid residues, with four putative membrane spanning domains and one asparagine-linked glycosylation site. Expression of PMP22 correlates with myelin formation and myelin-specific gene expression during sciatic nerve development and its down-regulation after nerve injury follows that of the myelin protein Po. In situ hybridization confirmed that PMP22 mRNA is synthesized by Schwann cells. PMP22 mRNA expression is clearly regulated by axon contact and is found mainly in the peripheral nervous system (PNS). The chapter discusses PMP22 and the inherited peripheral neuropathies in human, along with human peripheral neuropathies associated with mutations in other PNS myelin genes.

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.

Peripheral myelin protein‐22 expression in charcot‐marie‐tooth disease type 1a sural nerve biopsies

Peripheral myelin protein-22 (PMP22) is expressed in myelinating Schwann cells and shows significant homology to murine growth arrest-specific gene gas3. Charcot-Marie-Tooth disease type 1a (CMT1a) is a common hereditary demyelinating neuropathy. Recently it was demonstrated that the gene for PMP22 is duplicated in CMT1a patients. A gene dosage mechanism has been postulated to cause CMT1a. According to this hypothesis, the increase in copy number of PMP22 gene would lead to an elevated expression of PMP22 and thereby cause the demyelinating phenotype of CMT1a. In the present communication we analyzed PMP22 mRNA and protein expression in sural nerve biopsies from CMT1a patients and normal controls. We show that PMP22 mRNA expression in CMT1a is not uniform. We found both elevated as well as normal PMP22 mRNA levels in patients. Interestingly, the highest PMP22 mRNA level was found in the least affected patient. In contrast to the mRNA levels, PMP22 was clearly reduced in all CMT1a patients as shown by immunohistochemistry. Thus the CMT1a phenotype may not be strictly correlated with increased PMP22 mRNA and protein expression. Possible roles of PMP22 in the pathogenesis of CMT1a are discussed.