ArticleHuman molecular genetics2019
A nonsense mutation in myelin protein zero causes congenital hypomyelination neuropathy through altered P0 membrane targeting and gain of abnormal function.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 23 citations in OpenAlex.
- Charcot-Marie-Tooth disease and related neuropathies.Nature reviews. Disease primers · 2026Review
- Loss of C9orf72 impacts the peripheral neuromuscular system via immune dysregulation and accelerates the progression of amyotrophic lateral sclerosis in SOD-1 mutant mice.Journal of neuroinflammation · 2025Article
- On the synergy between myelin proteins P0, MBP, and P2 in peripheral nerve major dense line formation.The FEBS journal · 2025Article
- Review
- Qizhi Kebitong Formula Ameliorates Sciatic Nerve Injury in Streptozocin-induced Diabetic Mice through PERK/ATF4/CHOP Endoplasmic Reticulum Stress Signaling Pathway.Current pharmaceutical design · 2025Article
- Navigating the Landscape of CMT1B: Understanding Genetic Pathways, Disease Models, and Potential Therapeutic Approaches.International journal of molecular sciences · 2024Review
- Spatial selectivity of ATase inhibition in mouse models of Charcot-Marie-Tooth disease.Brain communications · 2024Article
- Myelin protein zero mutation-related hereditary neuropathies: Neuropathological insight from a new nerve biopsy cohort.Brain pathology (Zurich, Switzerland) · 2024Article
- Mechanisms and treatment strategies of demyelinating and dysmyelinating Charcot-Marie-Tooth disease.Neural regeneration research · 2023Review
- Canine models of Charcot-Marie-Tooth: MTMR2, MPZ, and SH3TC2 variants in golden retrievers with congenital hypomyelinating polyneuropathy.Neuromuscular disorders : NMD · 2023Article
- Disease Progression in Charcot-Marie-Tooth Disease Related to MPZ Mutations: A Longitudinal Study.Annals of neurology · 2023Article
- A novel mouse model of CMT1B identifies hyperglycosylation as a new pathogenetic mechanism.Human molecular genetics · 2022Article
- Mechanisms and Treatments in Demyelinating CMT.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Review
- Animal Models as a Tool to Design Therapeutical Strategies for CMT-like Hereditary Neuropathies.Brain sciences · 2021Review
- Therapeutic Development in Charcot Marie Tooth Type 1 Disease.International journal of molecular sciences · 2021Review
- Mutation update for myelin protein zero-related neuropathies and the increasing role of variants causing a late-onset phenotype.Journal of neurology · 2019Article
- Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy.Human molecular genetics · 2019Article
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Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
Abstract
Protein zero (P0) is the major structural protein in peripheral myelin, and mutations in the Myelin Protein Zero (Mpz) gene produce wide-ranging hereditary neuropathy phenotypes. To gain insight in the mechanisms underlying a particularly severe form, congenital hypomyelination (CH), we targeted mouse Mpz to encode P0Q215X, a nonsense mutation associated with the disease, that we show escapes nonsense mediated decay and is expressed in CH patient nerves. The knock-in mice express low levels of the resulting truncated protein, producing a milder phenotype when compared to patients, allowing to dissect the subtle pathogenic mechanisms occurring in otherwise very compromised peripheral myelin. We find that P0Q215X does not elicit an unfolded protein response, which is a key mechanism for other pathogenic MPZ mutations, but is instead in part aberrantly trafficked to non-myelin plasma membranes and induces defects in radial sorting of axons by Schwann cells. We show that the loss of the C-terminal Tyr-Ala-Met-Leu motif is responsible for P0 mislocalization, as its addition is able to restore correct P0Q215X trafficking in vitro. Lastly, we show that P0Q215X acts through dose-dependent gain of abnormal function, as wild-type P0 is unable to rescue the hypomyelination phenotype. Collectively, these data indicate that alterations at the premyelinating stage, linked to altered targeting of P0, may be responsible for CH, and that different types of gain of abnormal function produce the diverse neuropathy phenotypes associated with MPZ, supporting future allele-specific therapeutic silencing strategies.
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