Journal article
A nonsense mutation in myelin protein zero causes congenital hypomyelination neuropathy through altered P0 membrane targeting and gain of abnormal function
Human molecular genetics, Vol.28(1), pp.124-132
01/01/2019
DOI: 10.1093/hmg/ddy336
PMCID: PMC6298235
PMID: 30239779
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.
Details
- Title: Subtitle
- A nonsense mutation in myelin protein zero causes congenital hypomyelination neuropathy through altered P0 membrane targeting and gain of abnormal function
- Creators
- Pietro Fratta - UCL Institute of Neurology, Queen Square, London WC1N, UKFrancesca Ornaghi - IRCCS San Raffaele Scientific Institute, DIBIT, Milan, ItalyGabriele Dati - IRCCS San Raffaele Scientific Institute, DIBIT, Milan, ItalyDesirée Zambroni - IRCCS San Raffaele Scientific Institute, DIBIT, Milan, ItalyPaola Saveri - IRCCS San Raffaele Scientific Institute, DIBIT, Milan, ItalySophie Belin - Department of Neuroscience and Experimental Therapeutics, Albany Medical College Department of Neuroscience and Experimental Therapeutics, Albany, NY, USAPatrizia D’Adamo - IRCCS San Raffaele Scientific Institute, DIBIT, Milan, ItalyMichael Shy - Department of Neurology, University of Iowa, Iowa City, IA, USAAngelo Quattrini - IRCCS San Raffaele Scientific Institute, DIBIT, Milan, ItalyM Laura Feltri - IRCCS San Raffaele Scientific Institute, DIBIT, Milan, ItalyLawrence Wrabetz - IRCCS San Raffaele Scientific Institute, DIBIT, Milan, Italy
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.28(1), pp.124-132
- DOI
- 10.1093/hmg/ddy336
- PMID
- 30239779
- PMCID
- PMC6298235
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Publisher
- Oxford University Press
- Grant note
- ; MR/M008606/1 / ; ; ; ; R01 NS55256; R56NS096104 / ; ;
- Language
- English
- Date published
- 01/01/2019
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984070151102771
Metrics
23 Record Views