Molecular and clinical features of inherited neuropathies due to PMP22 duplication

Watila, Musa Mamman; Balarabe, Suleiman A.

doi:10.1016/j.jns.2015.05.037

Cited by 22 publications

(22 citation statements)

References 82 publications

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“…46 The 2 major causes leading to CMT disease are mutations in PMP22 and MFN2, which directly affect the myelin sheath and the axon. 47,48 Mutations in GDAP1 are associated with decreased mitochondrial fission activity (recessively inherited) or an impairment of mitochondrial fusion (dominantly inherited). 39,40,49 The expression of dominantly inherited mutated forms of GDAP1 lead to increased production of reactive oxygen species (ROS).…”

Section: Patients At T1 Patients At T2 P-valuementioning

confidence: 99%

Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome

et al. 2016

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Alcohol dependence is a severe disorder contributing substantially to the global burden of disease. Despite the detrimental consequences of chronic alcohol abuse and dependence, effective prevention strategies as well as treatment options are largely missing to date. Accumulating evidence suggests that gene-environment interactions, including epigenetic mechanisms, play a role in the etiology of alcohol dependence. A recent epigenome-wide study reported widespread alterations of DNA methylation patterns in alcohol dependent patients compared to control individuals. In the present study, we validate and replicate one of the top findings from this previous investigation in an independent cohort: the hypomethylation of GDAP1 in patients. To our knowledge, this is the first independent replication of an epigenome-wide finding in alcohol dependence. Furthermore, the AUDIT as well as the GSI score were negatively associated with GDAP1 methylation and we found a trend toward a negative association between GDAP1 methylation and the years of alcohol dependency, pointing toward a potential role of GDAP1 hypomethylation as biomarker for disease severity. In addition, we show that the hypomethylation of GDAP1 in patients reverses during a short-term alcohol treatment program, suggesting that GDAP1 DNA methylation could also serve as a potential biomarker for treatment outcome. Our data add to the growing body of knowledge on epigenetic effects in alcohol dependence and support GDAP1 as a novel candidate gene implicated in this disorder. As the role of GDAP1 in alcohol dependence is unknown, this novel candidate gene should be followed up in future studies.

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Section: Patients At T1 Patients At T2 P-valuementioning

confidence: 99%

Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome

et al. 2016

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“…The most common cause of CMT is from duplication of a 1.4 Mb segment on chromosome 17p11.2 harboring the PMP22 gene (CMT 1A), found in about 50% of all patients with CMT 8, 9, 10. Although the precise disease mechanism is not clear, it is suspected that overproduction of the PMP22 protein by the extra gene copy leads to abnormal Schwann cell development and myelin sheath maintenance, ultimately resulting in secondary axon loss and loss of sensory and motor function 11, 12. CMT is typically not life‐threatening but the patients’ symptoms impact their quality of life profoundly, and there is no effective treatment 7, 13.…”

Section: Introductionmentioning

confidence: 99%

“…[8][9][10] Although the precise disease mechanism is not clear, it is suspected that overproduction of the PMP22 protein by the extra gene copy leads to abnormal Schwann cell development and myelin sheath maintenance, ultimately resulting in secondary axon loss and loss of sensory and motor function. 11,12 CMT is typically not life-threatening but the patients' symptoms impact their quality of life profoundly, and there is no effective treatment. 7,13 Several pharmacological approaches for CMT1A have attempted to reduce PMP22 expression levels with progesterone antagonism 14 or ascorbic acid treatment.…”

Section: Introductionmentioning

confidence: 99%

Cell transplantation strategies for acquired and inherited disorders of peripheral myelin

Muhammad

Kim

Epifantseva

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo investigate transplantation of rat Schwann cells or human iPSC‐derived neural crest cells and derivatives into models of acquired and inherited peripheral myelin damage.MethodsPrimary cultured rat Schwann cells labeled with a fluorescent protein for monitoring at various times after transplantation. Human‐induced pluripotent stem cells (iPSCs) were differentiated into neural crest stem cells, and subsequently toward a Schwann cell lineage via two different protocols. Cell types were characterized using flow cytometry, immunocytochemistry, and transcriptomics. Rat Schwann cells and human iPSC derivatives were transplanted into (1) nude rats pretreated with lysolecithin to induce demyelination or (2) a transgenic rat model of dysmyelination due to PMP22 overexpression.ResultsRat Schwann cells transplanted into sciatic nerves with either toxic demyelination or genetic dysmyelination engrafted successfully, and migrated longitudinally for relatively long distances, with more limited axial migration. Transplanted Schwann cells engaged existing axons and displaced dysfunctional Schwann cells to form normal‐appearing myelin. Human iPSC‐derived neural crest stem cells and their derivatives shared similar engraftment and migration characteristics to rat Schwann cells after transplantation, but did not further differentiate into Schwann cells or form myelin.InterpretationThese results indicate that cultured Schwann cells surgically delivered to peripheral nerve can engraft and form myelin in either acquired or inherited myelin injury, as proof of concept for pursuing cell therapy for diseases of peripheral nerve. However, lack of reliable technology for generating human iPSC‐derived Schwann cells for transplantation therapy remains a barrier in the field.

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“…The biological functions of PMP22 proteins in mammalian cells are complex. PMP22 comprises an estimated 2% to 5% of the total myelin proteins in the peripheral nervous system (41). Its functional importance is highlighted by the fact that mutations in the PMP22 gene are the most common causes of inherited peripheral nerve disorders (20).…”

Section: Discussionmentioning

confidence: 99%

PMP22 Regulates Self-Renewal and Chemoresistance of Gastric Cancer Cells

Cai

Chen

Luo

et al. 2017

Molecular Cancer Therapeutics

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Cancer stem cells possess self-renewal and chemoresistance activities. However, the manner in which these features are maintained remains obscure. We sought to identify cell surface protein(s) that mark self-renewing and chemoresistant gastric cancer cells using the explorer antibody microarray. We identified PMP22, a target gene of the Wnt/β-catenin pathway, as the most upregulated cell surface protein in gastric cancer xenografts exposed to cisplatin (DDP). PMP22 expression was markedly upregulated in tumorspheric cells and declined with differentiation. Infecting gastric cancer cells with lentivirus expressing PMP22 shRNAs reduced proliferation, tumorsphere formation, and chemoresistance to cisplatin and in NOD/SCID mice. When combined with bortezomib, a PMP22 inhibitor, the chemotherapeutic sensitivity to cisplatin treatment was dramatically increased by inducing cell apoptosis in cultured cells and xenograft mouse models. Finally, mRNA expression levels of PMP22 were detected in 38 tumor specimens from patients who received six cycles of perioperative chemotherapy. A strong correlation between PMP22 level and tumor recurrence was revealed, thus showing a pivotal role of PMP22 in the clinical chemoresistance of gastric cancer. Our study is the first to show the role of PMP22 in gastric cancer stemness and chemoresistance and reveals a potential new target for the diagnosis and treatment of recurrent gastric cancer..

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Molecular and clinical features of inherited neuropathies due to PMP22 duplication

Cited by 22 publications

References 82 publications

Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome

Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome

Cell transplantation strategies for acquired and inherited disorders of peripheral myelin

PMP22 Regulates Self-Renewal and Chemoresistance of Gastric Cancer Cells

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