Genetic dosage compensation via co-occurrence of
            <i>PMP22</i>
            duplication and
            <i>PMP22</i>
            deletion

Hirt, Nina; Eggermann, Katja; Hyrenbach, Sonja; Lambeck, Johann; Busche, Andreas; Fischer, Judith; Rudnik‐Schöneborn, Sabine; Gaspar, Harald

doi:10.1212/wnl.0000000000001470

Cited by 12 publications

(12 citation statements)

References 6 publications

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“…High levels of PMP22 protein have also been reported in sural nerve biopsies from CMT1A patients [19,64]. Although the exact mechanism underlying the pathogenicity associated with expression of third copy of PMP22 is not yet clearly defined, it is well established that a correct stoichiometry of PMP22 protein is required to maintain compact myelin integrity [27,30]. Correction of PMP22 expression level reverses demyelination phenotype in a transgenic animal model [54] and the relevance of reducing PMP22 expression has been acknowledged as one potential therapeutic approach for CMT1A [47].…”

Section: C3-pmp22 Mice Show Altered Proteostasismentioning

confidence: 99%

Treatment with IFB-088 improves neuropathy in CMT1A and CMT1B mice

Bai

Treins

Volpi

et al. 2021

Preprint

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Charcot Marie Tooth diseases type 1A (CMT1A), caused by duplication of Peripheral Myelin Protein 22 (PMP22) gene, and CMT1B, caused by mutations in myelin protein zero (MPZ) gene are the two most common forms of demyelinating CMT (CMT1) and no treatments are available for either. Prior studies of the MpzSer63del mouse model of CMT1B have demonstrated that protein misfolding, endoplasmic reticulum (ER) retention and activation of the unfolded protein response (UPR) contributed to the neuropathy. Heterozygous patients with an arginine to cysteine mutation in MPZ (MPZR98C) develop a severe infantile form of CMT1B which is modeled by MpzR98C/+ mice that also show ER-stress and an activated UPR. C3-PMP22 mice are considered to effectively model CMT1A. Altered proteostasis, ER-stress and activation of the UPR have been demonstrated in mice carrying Pmp22 mutations. To determine whether enabling the ER-stress/UPR and readjusting protein homeostasis would effectively treat these models of CMT1B and CMT1A we administered Sephin1/IFB-088/icerguestat, a UPR modulator which showed efficacy in the MpzS63del model of CMT1B, to heterozygous MpzR98C and C3-PMP22 mice. Mice were analyzed by behavioral, neurophysiological, morphological and biochemical measures. Both MpzR98C/+ and C3-PMP22 mice improved in motor function and neurophysiology. Myelination, as demonstrated by g-ratios and myelin thickness, improved in CMT1B and CMT1A mice and markers of UPR activation returned towards wild type values. Taken together our results demonstrate the capability of IFB-088 to treat a second mouse model of CMT1B and a mouse model of CMT1A, the most common form of CMT. Given the recent benefits of IFB-088 treatment in Amyotrophic Lateral Sclerosis and Multiple Sclerosis animal models, these data demonstrate its potential in managing UPR and ER-stress for multiple mutations in CMT1 as well as in other neurodegenerative diseases.

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Section: C3-pmp22 Mice Show Altered Proteostasismentioning

confidence: 99%

Treatment with IFB-088 improves neuropathy in CMT1A and CMT1B mice

Bai

Treins

Volpi

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…Charcot-Marie-Tooth disease, a hereditary neuropathy, was one of the first human diseases shown to be due to duplication of a dosage-sensitive gene, PMP22 [ 16 , 17 ]. The fact that some phenotypically normal individuals carry both a duplication and a compensatory deletion of this gene supports the dosage sensitivity model rather than any other regulatory or structural effects as the underlying mechanism behind the disease condition [ 18 ]. In some cases, especially for intrinsically disordered proteins, the basis of pathogenicity may lie in an increased propensity for low-affinity off-target interactions at high concentrations [ 19 , 20 ].…”

Section: Dosage Sensitivitymentioning

confidence: 99%

Dosage-sensitive genes in evolution and disease

2017

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For a subset of genes in our genome a change in gene dosage, by duplication or deletion, causes a phenotypic effect. These dosage-sensitive genes may confer an advantage upon copy number change, but more typically they are associated with disease, including heart disease, cancers and neuropsychiatric disorders. This gene copy number sensitivity creates characteristic evolutionary constraints that can serve as a diagnostic to identify dosage-sensitive genes. Though the link between copy number change and disease is well-established, the mechanism of pathogenicity is usually opaque. We propose that gene expression level may provide a common basis for the pathogenic effects of many copy number variants.

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“…This gives no c17p12 in allele‐2 for copy 1 and 2 on allele‐1 to associate with and thereby eliminates the aberrant competition across the two chromatids. Removal of the aberrant competition may rescue the disease of CMT1A as reported by Hirt et al in the studied family 25. This hypothesis may be further tested by comparing dynamic changes of genomic structure and trans‐chromosomal/intrachromosomal interactions between cells from normal controls and cells from patients with CMT1A.…”

Section: Highly Variable Levels Of Pmp22mentioning

confidence: 62%

“…Perhaps, a counter‐argument is a study from Hirt et al25 In a single family with both HNPP and CMT1A alleles, HNPP and CMT1A alleles alone produced the expected diseases, whereas two sisters with compound heterozygous HNPP/CMT1A alleles are of no phenotype. Therefore, reducing the total PMP22 copy number from three to two is sufficient to “cure” CMT1A in human.…”

Section: Highly Variable Levels Of Pmp22mentioning

confidence: 99%

Caveats in the Established Understanding of CMT1A

2017

Ann Clin Transl Neurol

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Charcot‐Marie‐Tooth disease type‐1A (CMT1A) is one of the most common types of inherited peripheral nerve diseases. It is caused by the trisomy of chromosome 17p12 (c17p12), a large DNA segment of 1.4 Mb containing PMP22 plus eight other genes. The size of c17p12 is formidable for any cloning technique to manipulate, and thus precludes production of models in vitro and in vivo that can precisely recapitulate the genetic alterations in humans with CMT1A. This limitation and other factors have led to several assumptions, which have yet been carefully scrutinized, serving as key principles in our understanding of the disease. For instance, one extra copy of c17p12 in patients with CMT1A results in a higher gene dosage of PMP22, thereby expected to produce a higher level of PMP22 mRNA/proteins that cause the disease. However, there has been increasing evidence that PMP22 levels are highly variable among patients with CMT1A and may fall into the normal range at a given time point. This raises an alternative mechanism causing the disease by dysregulation of PMP22 expression or excessive fluctuation of PMP22 levels, not the absolute increase of PMP22. This has become a pressing issue since recent clinical trials using ascorbic acid failed to alter the clinical outcome of CMT1A patients, leaving no effective therapy for the disease. In this article, we will discuss how this fundamental issue might be investigated. In addition, several other key issues in CMT1A will be discussed, including potential mechanisms responsible for the uniform slowing of conduction velocities. A clear understanding of these issues could radically change how therapies should be developed against CMT1A.

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Genetic dosage compensation via co-occurrence of PMP22 duplication and PMP22 deletion

Cited by 12 publications

References 6 publications

Treatment with IFB-088 improves neuropathy in CMT1A and CMT1B mice

Treatment with IFB-088 improves neuropathy in CMT1A and CMT1B mice

Dosage-sensitive genes in evolution and disease

Caveats in the Established Understanding of CMT1A

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