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

Suter, Ueli; Snipes, G. Jackson; R, Schoener-Scott; Welcher, Andrew A.; Pareek, Sangeeta; Lupski, James R.; Murphy, R. A.; Shooter, E. M.; Patel, Pritty

doi:10.1016/s0021-9258(18)47318-8

Cited by 168 publications

(24 citation statements)

References 63 publications

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“…PMP22 is most highly expressed in peripheral nerve, and its transcripts are among the most abundantly expressed genes in mature Schwann cells after a dramatic induction during myelination. Initial studies of Pmp22 regulation had focused on Pmp22 promoters (Suter et al, 1994). The two major promoters P1 and P2 drive expression of two alternate noncoding exons (1A or 1B respectively) and these transcripts are approximately in 3:1 ratio in rodents and 1:1 ratio in human Schwann cells (as recently confirmed in gtexportal.org).…”

Section: Pmp22 Gene Regulationmentioning

confidence: 96%

Regulating PMP22 expression as a dosage sensitive neuropathy gene

2020

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Structural variation in the human genome has emerged as a major cause of disease as genomic data have accumulated. One of the most common structural variants associated with human disease causes the heritable neuropathy known as Charcot-Marie-Tooth (CMT) disease type 1A. This 1.4 Mb duplication causes nearly half of the CMT cases that are genetically diagnosed. The PMP22 gene is highly induced in Schwann cells during development, although its precise role in myelin formation and homeostasis is still under active investigation. The PMP22 gene can be considered as a nucleoprotein complex with enzymatic activity to produce the PMP22 transcript, and the complex is allosterically regulated by transcription factors that respond to intracellular signals and epigenomic modifications. The control of PMP22 transcript levels has been one of the major therapeutic targets of therapy development, and this review summarizes those approaches as well as efforts to characterize the regulation of the PMP22 gene.

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Section: Pmp22 Gene Regulationmentioning

confidence: 96%

Regulating PMP22 expression as a dosage sensitive neuropathy gene

2020

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“…For quantification of Lonaprisan effect on Plp1 expression, normalization was performed against the nonsteroid-regulated, non-myelin-related, and ubiquitously expressed exon 1B transcript of Pmp22. 39,53,54,55 Bax, Jun, and Casp7 mRNA expression was normalized against the mean of Rplp0, Ppia, and Atp5b mRNA expression. Primer sequences can be provided upon request.…”

Section: Rna Expression Analysesmentioning

confidence: 99%

Progesterone Antagonist Therapy in a Pelizaeus-Merzbacher Mouse Model

Prukop

Epplen

Nientiedt

et al. 2014

The American Journal of Human Genetics

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Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating disease, characterized by ataxia, intellectual disability, epilepsy, and premature death. In the majority of cases, PMD is caused by duplication of PLP1 that is expressed in myelinating oligodendrocytes. Despite detailed knowledge of PLP1, there is presently no curative therapy for PMD. We used a Plp1 transgenic PMD mouse model to test the therapeutic effect of Lonaprisan, an antagonist of the nuclear progesterone receptor, in lowering Plp1 mRNA overexpression. We applied placebo-controlled Lonaprisan therapy to PMD mice for 10 weeks and performed the grid slip analysis to assess the clinical phenotype. Additionally, mRNA expression and protein accumulation as well as histological analysis of the central nervous system were performed. Although Plp1 mRNA levels are increased 1.8-fold in PMD mice compared to wild-type controls, daily Lonaprisan treatment reduced overexpression at the RNA level to about 1.5-fold, which was sufficient to significantly improve the poor motor phenotype. Electron microscopy confirmed a 25% increase in the number of myelinated axons in the corticospinal tract when compared to untreated PMD mice. Microarray analysis revealed the upregulation of proapoptotic genes in PMD mice that could be partially rescued by Lonaprisan treatment, which also reduced microgliosis, astrogliosis, and lymphocyte infiltration.

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“…26,27 More recently, the PMP22 promoter has been shown to contain two cyclic adenosine monophosphate response element binding protein (CREB) binding sites, 28 and treatments that elevate Schwann cell cyclic adenosine monophosphate content stimulate PMP22 gene expression by cultured Schwann cells. 29,30 Although the extent to which cyclic adenosine monophosphate drives Schwann cell PMP22 synthesis in intact nerves is not known, these observations raise the possibility that interfering with such driving would have therapeutic value in Charcot-Marie-Tooth disease type 1A. Based on the observation that ascorbic acid (vitamin C) inhibits the stimulation of the PMP22 promoter by dibutyryl cyclic adenosine monophosphate (AMP) in cultured Schwann cells, Passage et al treated young adult PMP22-transgenic mice with a weekly oral dose of vitamin C corresponding to the maximal dose approved for treatment of humans with vitamin C deficiency.…”

Section: Charcot-marie-tooth Disease Type 1amentioning

confidence: 99%

New Treatments for Denervating Diseases

Pleasure

2005

J Child Neurol

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There has been considerable recent progress in understanding mechanisms by which gene mutations cause degeneration of motoneurons and peripheral nerves. Novel therapies inspired by these insights have begun to yield promising results in mouse models of these genetic diseases. Among these have been the use of small molecules or proteins to suppress gain-of-function mutations (eg, ascorbic acid for Charcot-Marie-Tooth disease type 1A) or to restore enzyme activities that are deficient because of loss-of-function mutations (eg, treatment of Fabry's disease with recombinant alpha-galactosidase or with low-molecular-weight alpha-galactosidase chaperones and treatment of spinal muscular atrophy with phenylbutyrate). Some of these therapies are already being tested in humans. Equally exciting is the prospect that small molecules and proteins will be identified that exert potent therapeutic effects in a broad spectrum of inherited and acquired motoneuron and peripheral nerve disorders.

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

Cited by 168 publications

References 63 publications

Regulating PMP22 expression as a dosage sensitive neuropathy gene

Regulating PMP22 expression as a dosage sensitive neuropathy gene

Progesterone Antagonist Therapy in a Pelizaeus-Merzbacher Mouse Model

New Treatments for Denervating Diseases

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