Journal article
Loss of function MPZ mutation causes milder CMT1B neuropathy
Journal of the peripheral nervous system, Vol.26(2), pp.177-183
2021
DOI: 10.1111/jns.12452
PMID: 33960567
Abstract
Mutations in Myelin Protein Zero (MPZ) cause CMT1B, the second leading cause of CMT1. Many of the >200 mutations cause neuropathy through a toxic gain of function by the mutant protein such as ER retention, activation of the Unfolded Protein Response (UPR) or disruption of myelin compaction. While there is extensive literature on the loss of function consequences of MPZ in heterozygous Mpz +/− null mice, there is little known of the consequences of MPZ haploinsufficiency in humans. We identified six patients from different families with p.Tyr68Ter or p.Asp104fs heterozygous mutations of MPZ that are predicted to cause a premature termination and nonsense mediated decay of the mutant allele. Five patients were evaluated in Milan and one in Iowa City; all should be haploinsufficient for MPZ. Patients were evaluated clinically and by electrophysiology. Sensory ataxia dominated the clinical presentation with only mild weakness present in five of the six patients. Symptoms presented in adulthood in all patients and only one individual had a CMTNSv2 >5. Deep tendon reflexes were absent in all patients. Patients with likely MPZ loss of function due to mutations that cause haplodeficiency in MPZ have a mild, predominantly large fiber sensory neuropathy that serves as a human equivalent to the neuropathy observed in heterozygous Mpz null mice. Successful therapeutic approaches in treating Mpz deficient mice may be candidates for trials in these and similar patients.
Details
- Title: Subtitle
- Loss of function MPZ mutation causes milder CMT1B neuropathy
- Creators
- Paige Howard - Roy and Lucille Carver College of Medicine, University of Iowa Iowa City Iowa USAShawna M. E Feely - University of Iowa Healthcare Neurology Iowa City Iowa USATiffany Grider - University of Iowa Healthcare Neurology Iowa City Iowa USAAlexa Bacha - Roy and Lucille Carver College of Medicine, University of Iowa Iowa City Iowa USAMarina Scarlato - Institute of Experimental Neurology (InSpe) and Division of Neuroscience IRCCS Ospedale San Raffaele Milano ItalyRaffaella Fazio - Institute of Experimental Neurology (InSpe) and Division of Neuroscience IRCCS Ospedale San Raffaele Milano ItalyAngelo Quattrini - Institute of Experimental Neurology (InSpe) and Division of Neuroscience IRCCS Ospedale San Raffaele Milano ItalyMichael E Shy - Roy and Lucille Carver College of Medicine, University of Iowa Iowa City Iowa USAStefano C Previtali - Institute of Experimental Neurology (InSpe) and Division of Neuroscience IRCCS Ospedale San Raffaele Milano Italy
- Resource Type
- Journal article
- Publication Details
- Journal of the peripheral nervous system, Vol.26(2), pp.177-183
- DOI
- 10.1111/jns.12452
- PMID
- 33960567
- ISSN
- 1085-9489
- eISSN
- 1529-8027
- Grant note
- DOI: 10.13039/100002721, name: Charcot-Marie-Tooth Association, award: 2U54NS065712‐08; DOI: 10.13039/100005202, name: Muscular Dystrophy Association; DOI: 10.13039/100000065, name: National Institute of Neurological Disorders and Stroke, award: U54NS0e65712; DOI: 10.13039/100009647, name: Ministry of Health, award: EJPRD19‐118, RF‐2016‐02361246
- Language
- English
- Date published
- 2021
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984077785002771
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