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Orphanet J Rare Dis. 2019 Aug 14;14(1):197. doi: 10.1186/s13023-019-1162-x.

Peripheral myelin protein 2 - a novel cluster of mutations causing Charcot-Marie-Tooth neuropathy.

Author information

1
Molecular Neurogenomics group, VIB-UAntwerp Centre for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
2
Department of Neurology, Medical University-Sofia, Sofia, Bulgaria.
3
Department of Neurology, Heinrich Heine University Duesseldorf, Medical Faculty, Duesseldorf, Germany.
4
Department of Medical Chemistry and Biochemistry, Medical University-Sofia, Sofia, Bulgaria.
5
Neurodegenerative Brain Diseases group, VIB-UAntwerp Centre for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
6
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
7
Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria.
8
Molecular Neurogenomics group, VIB-UAntwerp Centre for Molecular Neurology, University of Antwerp, Antwerp, Belgium. albena.jordanova@uantwerpen.vib.be.
9
Department of Medical Chemistry and Biochemistry, Medical University-Sofia, Sofia, Bulgaria. albena.jordanova@uantwerpen.vib.be.

Abstract

BACKGROUND:

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder characterized by wide clinical, genetic and pathomechanistic heterogeneity. Recently, the gene encoding peripheral myelin protein 2 (PMP2) was identified as a novel cause for CMT neuropathy with three mutations that structurally cluster together (p.Ile43Asn, p.Thr51Pro, p.Ile52Thr) reported in five families.

RESULTS:

Using whole exome sequencing and cohort screening we identified two novel missense substitutions in PMP2 in Bulgarian (p.Met114Thr, c.341C > T) and German (p.Val115Ala, c.344 T > C) families. The mutations affect adjacent and highly conserved amino acid residues outside of the known mutation-rich region in the protein. Crystal structure analysis positions the affected residues within a cluster of highly conserved fatty acid coordinating residues implying their functional significance. The clinical, electrophysiological and imaging features in both families were consistent with a childhood onset polyneuropathy with variable patterns of demyelination, slow to very slow progression, and most severe involvement of the peroneal muscles.

CONCLUSIONS:

We expand the genetic and phenotypic spectrum of PMP2-related peripheral neuropathy. Our findings reveal a second mutational cluster in the protein.

KEYWORDS:

CMT; Cluster; Demyelinating; Novel; PMP2

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