scholarly journals AAV1.NT-3 gene therapy for X-linked Charcot–Marie–Tooth neuropathy type 1

Gene Therapy ◽  
2021 ◽  
Author(s):  
Burcak Ozes ◽  
Morgan Myers ◽  
Kyle Moss ◽  
Jennifer Mckinney ◽  
Alicia Ridgley ◽  
...  
Keyword(s):  
Compound Muscle Action Potential ◽  
Functional Decline ◽  
Gene Encoding ◽  
Charcot Marie Tooth ◽  
Muscle Action Potential ◽  
Neurotrophin 3 ◽  
Junction Protein ◽  
Myelin Thickness ◽  
Gap Junction Protein

AbstractX-linked Charcot-Marie-Tooth neuropathy (CMTX) is caused by mutations in the gene encoding Gap Junction Protein Beta-1 (GJB1)/Connexin32 (Cx32) in Schwann cells. Neurotrophin-3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulating axon regeneration and myelination. Improvements in these parameters have been shown previously in a CMT1 model, TremblerJ mouse, with NT-3 gene transfer therapy. For this study, scAAV1.tMCK.NT-3 was delivered to the gastrocnemius muscle of 3-month-old Cx32 knockout (KO) mice. Measurable levels of NT-3 were found in the serum at 6-month post gene delivery. The outcome measures included functional, electrophysiological and histological assessments. At 9-months of age, NT-3 treated mice showed no functional decline with normalized compound muscle action potential amplitudes. Myelin thickness and nerve conduction velocity significantly improved compared with untreated cohort. A normalization toward age-matched wildtype histopathological parameters included increased number of Schmidt-Lanterman incisures, and muscle fiber diameter. Collectively, these findings suggest a translational application to CMTX1.

scholarly journals Recurrent Episodes of Stroke-Like Symptoms in a Patient with Charcot-Marie-Tooth Neuropathy X Type 1

2015 ◽  
Vol 7 (3) ◽  
pp. 247-252 ◽  
Author(s):  
Ning Wu ◽  
Sarita Said ◽  
Shyamsunder Sabat ◽  
Matthew Wicklund ◽  
Mark C. Stahl
Keyword(s):  
English Language ◽  
Case Reports ◽  
Sensory Neuropathy ◽  
Neurological Deficits ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Junction Protein ◽  
Gap Junction Protein ◽  
Magnetic Resonance Imaging Mri

Charcot-Marie-Tooth disease (CMT), also known as hereditary motor sensory neuropathy, is a heterogeneous group of disorders best known for causing inherited forms of peripheral neuropathy. The X-linked form, CMTX1, is caused by mutations in the gap junction protein beta 1 (GJB1) gene, expressed both by peripheral Schwann cells and central oligodendrocytes. Central manifestations are known but are rare, and there are few case reports of leukoencephalopathy with transient or persistent neurological deficits in patients with this CMT subtype. Here, we report the case of a man with multiple male and female family members affected by neuropathy who carries a pathologic mutation in GJB1. He has experienced three transient episodes with variable neurological deficits over the course of 7 years with corresponding changes on magnetic resonance imaging (MRI). This case illustrates CMT1X as a rare cause of transient neurological deficit and demonstrates the evolution of associated reversible abnormalities on MRI over time. To the best of our knowledge, this report provides the longest period of serial imaging in a single patient with this condition in the English language literature.

scholarly journals Prevalence of congenital non syndromic hearing loss among offspring of consanguineous marriage: a pilot study

2020 ◽  
Vol 6 (5) ◽  
pp. 874
Author(s):  
Gangadhar K. S. ◽  
Geetha Bhaktha ◽  
Manjula B. ◽  
Nageshwari P.
Keyword(s):  
Hearing Loss ◽  
Consanguineous Marriage ◽  
Gene Encoding ◽  
Single Nucleotide ◽  
Junction Protein ◽  
Study Population ◽  
Syndromic Hearing Loss ◽  
Gap Junction Protein ◽  
Polymerase Chain ◽  
Recessive Defect

<p class="abstract"><strong>Background:</strong> Mutations in the gene encoding the gap-junction protein connexin-26, is understood to be the most important cause of non-syndromic hearing loss (NSHL). An attempt to identify the single nucleotide polymorphism (SNP) for W24X mutation was done.  Consanguineous marriage was seen among the NSHL subjects.</p><p class="abstract"><strong>Methods:</strong> SNP was identified using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR).  Forty-five subjects were screened for congenital hearing loss. Twenty subjects matched the inclusion criteria and were included in the study.</p><p class="abstract"><strong>Results:</strong> 5 out of 20 subjects were found to have mutation i.e., 25%. Though consanguinity is known to cause autosomal recessive defect, the same could not be depicted in this study.</p><p class="abstract"><strong>Conclusions:</strong> 25% of the study population had a mutation in their gene and the rest though had consanguineous marriage had not been affected genotypically.</p>

Identification of a mutation in GJB6 gene, encoding a gap junction protein Cx30, in a family with Clouston syndrome

2013 ◽  
Vol 69 (2) ◽  
pp. e55
Author(s):  
Atsushi Fujimoto ◽  
Mazen Kurban ◽  
Motonobu Nakamura ◽  
Muhammad Farooq ◽  
Hiroki Fujikawa ◽  
...  
Keyword(s):  
Gap Junction ◽  
Gene Encoding ◽  
Junction Protein ◽  
Gap Junction Protein

scholarly journals A dominant connexin43 mutant does not have dominant effects on gap junction coupling in astrocytes

2010 ◽  
Vol 6 (4) ◽  
pp. 213-223 ◽  
Author(s):  
Sameh Wasseff ◽  
Charles K. Abrams ◽  
Steven S. Scherer
Keyword(s):  
Gap Junction ◽  
Lucifer Yellow ◽  
Brain Slices ◽  
Gene Encoding ◽  
Transfected Cells ◽  
Dominant Phenotype ◽  
Sulforhodamine B ◽  
Junction Protein ◽  
The Central Nervous System ◽  
Gap Junction Protein

Dominant mutations in GJA1, the gene encoding the gap junction protein connexin43 (Cx43), cause oculodentodigital dysplasia (ODDD), a syndrome affecting multiple tissues, including the central nervous system (CNS). We investigated the effects of the G60S mutant, which causes a similar, dominant phenotype in mice (Gja1Jrt/+). Astrocytes in acute brain slices from Gja1Jrt/+ mice transfer sulforhodamine-B comparably to that in their wild-type (WT) littermates. Further, astrocytes and cardiomyocytes cultured from Gja1Jrt/+ mice showed a comparable transfer of lucifer yellow to those from WT mice. In transfected cells, the G60S mutant formed gap junction (GJ) plaques but not functional channels. In co-transfected cells, the G60S mutant co-immunoprecipitated with WT Cx43, but did not diminish GJ coupling as measured by dual patch clamp. Thus, whereas G60S has dominant effects, it did not appreciably reduce GJ coupling.

scholarly journals Quantitative validation of GJC1 promoter hypermethylation in benign and malignant colorectal tumors

2011 ◽  
Vol 18 (6) ◽  
pp. C31-C34 ◽  
Author(s):  
Deeqa Ahmed ◽  
Ragnhild A Lothe ◽  
Edgar Rivedal ◽  
Guro E Lind
Keyword(s):  
Cpg Island ◽  
Promoter Hypermethylation ◽  
Tumor Location ◽  
Colorectal Tumors ◽  
Cpg Island Methylator Phenotype ◽  
Gene Encoding ◽  
Junction Protein ◽  
Quantitative Validation ◽  
Gap Junction Protein ◽  
Methylator Phenotype

We have previously shown that the gap junction protein γ 1 (GJC1) gene, encoding the connexin-45 protein, is inactivated by promoter hypermethylation in colorectal cancer. This was confirmed in a recent Endocrine-Related Cancer publication analyzing a limited number of samples. The aim of this study was to analyze GJC1 in a larger clinical cohort (n=485) and to assess whether or not the promoter hypermethylation was associated with clinical or pathological features. The methylation of GJC1 was confirmed to be tumor specific and was observed in 33% of colorectal cancers and 12% of adenomas. The methylation was strongly associated with BRAF mutations (P=5.64×10−13) as well as with proximal tumor location (P=1.42×10−3), features compatible with a CpG island methylator phenotype.

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