Demyelinating CMT–what’s known, what’s new and what’s in store?

Brennan, Kathryn M.; Bai, Yunhong; Shy, Michael E.

doi:10.1016/j.neulet.2015.01.059

Cited by 53 publications

(56 citation statements)

References 146 publications

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“…The largest group of IPNs includes hereditary motor and sensory neuropathies (HMSN) or Charcot–Marie–Tooth (CMT) diseases, with the most severe forms also known as Dejerine-Sottas syndrome (DSS) and congenital hypomyelination (CH) (Baets et al, 2014; Jerath and Shy, 2015). At least 80 different genes have been linked to IPNs/CMTs, many of which are important for proper synthesis, structure and function of the myelin sheath (Brennan et al, 2015). Mutations in P0, PMP22 and Connexin32 (Cx32), the main structural proteins of PNS myelin, altogether represent the vast majority of all CMT cases (Jerath and Shy, 2015).…”

Section: Erqc and Charcot-marie-tooth (Cmt) Neuropathiesmentioning

confidence: 99%

Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders

Volpi¹,

Touvier²,

D’Antonio³

2017

Front. Mol. Neurosci.

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Reaching the correct three-dimensional structure is crucial for the proper function of a protein. The endoplasmic reticulum (ER) is the organelle where secreted and transmembrane proteins are synthesized and folded. To guarantee high fidelity of protein synthesis and maturation in the ER, cells have evolved ER-protein quality control (ERQC) systems, which assist protein folding and promptly degrade aberrant gene products. Only correctly folded proteins that pass ERQC checkpoints are allowed to exit the ER and reach their final destination. Misfolded glycoproteins are detected and targeted for degradation by the proteasome in a process known as endoplasmic reticulum-associated degradation (ERAD). The excess of unstructured proteins in the ER triggers an adaptive signal transduction pathway, called unfolded protein response (UPR), which in turn potentiates ERQC activities in order to reduce the levels of aberrant molecules. When the situation cannot be restored, the UPR drives cells to apoptosis. Myelin-forming cells of the central and peripheral nervous system (oligodendrocytes and Schwann cells) synthesize a large amount of myelin proteins and lipids and therefore are particularly susceptible to ERQC failure. Indeed, deficits in ERQC and activation of ER stress/UPR have been implicated in several myelin disorders, such as Pelizaeus-Merzbacher and Krabbe leucodystrophies, vanishing white matter disease and Charcot-Marie-Tooth neuropathies. Here we discuss recent evidence underlying the importance of proper ERQC functions in genetic disorders of myelinating glia.

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Section: Erqc and Charcot-marie-tooth (Cmt) Neuropathiesmentioning

confidence: 99%

Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders

Volpi¹,

Touvier²,

D’Antonio³

2017

Front. Mol. Neurosci.

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“…CMT1 often manifests early in life, with onset by 10 years of age in more than 60% of patients (5), and can be debilitating to the point of rendering patients wheelchair-bound. To date, over 80 genes have been implicated in CMT disease with over 20 implicated in demyelinating forms (CMT1) (6). Genes mutated in CMT1 include those encoding myelin proteins (e.g.…”

Section: Introductionmentioning

confidence: 99%

SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locusMTMR2

Fogarty¹,

Brewer

Rodríguez-Molina³

et al. 2016

Hum. Mol. Genet.

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Schwann cells are the myelinating glia of the peripheral nervous system and dysfunction of these cells causes motor and sensory peripheral neuropathy. The transcription factor SOX10 is critical for Schwann cell development and maintenance, and many SOX10 target genes encode proteins required for Schwann cell function. Loss-of-function mutations in the gene encoding myotubularin-related protein 2 (MTMR2) cause Charcot-Marie-Tooth disease type 4B1 (CMT4B1), a severe demyelinating peripheral neuropathy characterized by myelin outfoldings along peripheral nerves. Previous reports indicate that MTMR2 is ubiquitously expressed making it unclear how loss of this gene causes a Schwann cell-specific phenotype. To address this, we performed computational and functional analyses at MTMR2 to identify transcriptional regulatory elements important for Schwann cell expression. Through these efforts, we identified an alternative, SOX10-responsive promoter at MTMR2 that displays strong regulatory activity in immortalized rat Schwann (S16) cells. This promoter directs transcription of a previously unidentified MTMR2 transcript that is enriched in mouse Schwann cells compared to immortalized mouse motor neurons (MN-1), and is predicted to encode an N-terminally truncated protein isoform. The expression of the endogenous transcript is induced in a heterologous cell line by ectopically expressing SOX10, and is nearly ablated in Schwann cells by impairing SOX10 function. Intriguingly, overexpressing the two MTMR2 protein isoforms in HeLa cells revealed that both localize to nuclear puncta and the shorter isoform displays higher nuclear localization compared to the longer isoform. Combined, our data warrant further investigation of the truncated MTMR2 protein isoform in Schwann cells and in CMT4B1 pathogenesis.

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“…In 1968, Peter Dyck and Edward Lambert proposed the use of clinicopathological data, natural history, inheritance pattern and motor nerve conduction velocities (MNCV) measured on median nerves to categorise the various forms of PMA 19 20. Since then, the electrophysiological dichotomy of demyelinating (MNCV <38 m/s in median nerve) and axonal (MNCV >38 m/s in median nerve) hereditary neuropathies is the mainstay of the classification, although it is well known that both groups are heterogeneous 21. With time, it appeared reasonable to individualise an ‘intermediate form’, which corresponds to patients who have MNCV between 30 and 40 m/s (in median nerve) 22 23…”

Section: Cmt Disease: Historical Perspectivesmentioning

confidence: 99%

“…In CMTX, numbers are used instead of letters to categorise the subcategory of CMT (eg, CMTX1 and CMTX2). Progressively, we have learnt that mutations in a same gene may cause different CMT phenotypes; for example, mutations in MPZ usually present as a dominant demyelinating form (CMT1B), more rarely as a dominant axonal form (CMT2I/J) and also as DSS 21. It also became evident that the same gene may harbour mutations characterised by different patterns of transmission; for example, mutations in NEFL and in GDAP1 may lead to AD-CMT or AR-CMT 66…”

Section: Cmt Disease: What Are the Limits Of The Current Classificatimentioning

confidence: 99%