Dataset Information

Histopathology of the Inner Ear in Charcot-Marie-Tooth Syndrome Caused by a Missense Variant (p.Thr65Ala) in the MPZ Gene.

ABSTRACT: Charcot-Marie-Tooth (CMT) syndrome is a clinically and genetically heterogeneous group of neuropathies affecting both peripheral motor and sensory nerves. Progressive sensorineural hearing loss, vestibular abnormalities, and dysfunction of other cranial nerves have been described. This is the second case report of otopathology in a patient with CMT syndrome. Molecular genetic testing of DNA obtained at autopsy revealed a missense variant in the MPZ gene (p.Thr65Ala), pathogenic for an autosomal-dominant form of CMT1B. The temporal bones were also prepared for light microscopy by hematoxylin and eosin and Gömöri trichome stains, and immunostaining for anti-myelin protein zero. Pathology was consistent with a myelinopathy of the auditory, vestibular, and facial nerves bilaterally. The pathophysiology of cranial nerve dysfunction in CMT is unknown. Findings in the current case suggested, at least in cranial nerves 7 and 8, that a myelinopathy may be causative.

SUBMITTER: Nadol JB

PROVIDER: S-EPMC6421093 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Histopathology of the Inner Ear in Charcot-Marie-Tooth Syndrome Caused by a Missense Variant (p.Thr65Ala) in the MPZ Gene.

Nadol Joseph B JB Hedley-Whyte E Tessa ET Amr Sami Samir SS O Apos Malley Jennifer T JT Kamakura Takefumi T

Audiology & neuro-otology 20180101 6

Charcot-Marie-Tooth (CMT) syndrome is a clinically and genetically heterogeneous group of neuropathies affecting both peripheral motor and sensory nerves. Progressive sensorineural hearing loss, vestibular abnormalities, and dysfunction of other cranial nerves have been described. This is the second case report of otopathology in a patient with CMT syndrome. Molecular genetic testing of DNA obtained at autopsy revealed a missense variant in the MPZ gene (p.Thr65Ala), pathogenic for an autosomal- ...[more]

PMID: 30677751

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Project description:Mutations in MPZ (myelin protein zero) can cause demyelinating early-onset Charcot-Marie-Tooth type 1B disease or later onset type 2I/J disease characterized by axonal degeneration, reflecting the diverse roles of MPZ in Schwann cells. MPZ holds apposing membranes of the myelin sheath together, with the adhesion role fulfilled by its extracellular immunoglobulin-like domain (IgMPZ), which oligomerizes. Models for how the IgMPZ might form oligomeric assemblies has been extrapolated from a protein crystal structure in which individual rat IgMPZ subunits are packed together under artificial conditions, forming three weak interfaces. One interface organizes the IgMPZ into tetramers, a second 'dimer' interface links tetramers together across the intraperiod line, and a third hydrophobic interface that mediates binding to lipid bilayers or the same hydrophobic surface on another IgMPZ domain. Presently, there are no data confirming whether the proposed IgMPZ interfaces actually mediate oligomerization in solution, whether they are required for the adhesion activity of MPZ, whether they are important for myelination, or whether their loss results in disease. We performed nuclear magnetic resonance spectroscopy and small angle X-ray scattering analysis of wild-type IgMPZ as well as mutant forms with amino acid substitutions designed to interrupt its presumptive oligomerization interfaces. Here, we confirm the interface that mediates IgMPZ tetramerization, but find that dimerization is mediated by a distinct interface that has yet to be identified. We next correlated different types of Charcot-Marie-Tooth disease symptoms to subregions within IgMPZ tetramers. Variants causing axonal late-onset disease (CMT2I/J) map to surface residues of IgMPZ proximal to the transmembrane domain. Variants causing early-onset demyelinating disease (CMT1B) segregate into two groups: one is described by variants that disrupt the stability of the Ig-fold itself and are largely located within the core of the IgMPZ domain; whereas another describes a region on the surface of IgMPZ tetramers, accessible to protein interactions. Computational docking studies predict that this latter disease-relevant subregion may potentially mediate dimerization of IgMPZ tetramers.

Dataset Information

Histopathology of the Inner Ear in Charcot-Marie-Tooth Syndrome Caused by a Missense Variant (p.Thr65Ala) in the MPZ Gene.

Publications

Histopathology of the Inner Ear in Charcot-Marie-Tooth Syndrome Caused by a Missense Variant (p.Thr65Ala) in the MPZ Gene.

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