Charcot-Marie-Tooth disease type 4C (CMT4C) is one of the commonest autosomal recessive inherited peripheral neuropathies and is associated with mutations in the Rab11 effector, SH3TC2. Disruption of the SH3TC2-Rab11 interaction is the molecular abnormality underlying this disease. However, why SH3TC2 mutations cause an isolated demyelinating neuropathy remains unanswered. Here we show that SH3TC2 is an exclusive Schwann cell protein expressed late in myelination and is downregulated following denervation suggesting a functional role in myelin sheath maintenance. We support our data with an evolutionary cell biological analysis showing that the SH3TC2 gene, and its paralogue SH3TC1, are derived from an ancestral homologue, the duplication of which occurred in the common ancestor of jawed vertebrates, coincident with the appearance of Schwann cells and peripheral axon myelination. Furthermore, we report that SH3TC2 associates with integrin-α6, suggesting that aberrant Rab11-dependent endocytic trafficking of this critical laminin receptor in myelinated Schwann cells is connected to the demyelination seen in affected nerves. Our study therefore highlights the inherent evolutionary link between SH3TC2 and peripheral nerve myelination, pointing also towards a molecular mechanism underlying the specific demyelinating neuropathy that characterizes CMT4C.
Pubmed ID: 27068304 RIS Download
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Public database with millions of high-resolution images showing the spatial distribution of proteins in different normal human tissues and cancer types, as well as different human cell lines. The data is released together with application-specific validation performed for each antibody, including immunohistochemisty, Western blot analysis and, for a large fraction, a protein array assay and immunofluorescent based confocal microscopy. The database has been developed in a gene-centric manner with the inclusion of all human genes predicted from genome efforts. Search functionalities allow for complex queries regarding protein expression profiles, protein classes and chromosome location. Antibodies included have been analyzed using a standardized protocol in a single attempt without further efforts to optimize the procedure and therefore it cannot be excluded that certain observed binding properties are due to technical rather than biological reasons and that further optimization could result in a different outcome. Submission of antibodies: The Swedish Human Proteome Atlas (HPA) program, invites submission of antibodies from both academic and commercial sources to be included in the human protein atlas. All antibodies will be validated by the HPA-program by a standard procedure and antibodies that are accepted will be use in the tissue- profiling program to generate high-resolution immunohistochemistry images representing a wide spectrum of normal tissues and cancer types.
View all literature mentionsWeb application to search protein databases using a translated nucleotide query. Translated BLAST services are useful when trying to find homologous proteins to a nucleotide coding region. Blastx compares translational products of the nucleotide query sequence to a protein database. Because blastx translates the query sequence in all six reading frames and provides combined significance statistics for hits to different frames, it is particularly useful when the reading frame of the query sequence is unknown or it contains errors that may lead to frame shifts or other coding errors. Thus blastx is often the first analysis performed with a newly determined nucleotide sequence and is used extensively in analyzing EST sequences. This search is more sensitive than nucleotide blast since the comparison is performed at the protein level.
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View all literature mentionsA Bayesian Monte Carlo Markov Chain (MCMC) sampler software for phylogenetic reconstruction. Its main distinguishing feature is the underlying probabilistic model, CAT (Lartillot and Philippe, 2004). CAT is an infinite mixture model accounting for site-specific amino-acid or nucleotide preferences. It is well suited to phylogenomic studies using large multigene alignments.
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View all literature mentionsMultiple sequence alignment method with reduced time and space complexity.Multiple sequence alignment with high accuracy and high throughput. Data analysis service for multiple sequence comparison by log- expectation.
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View all literature mentionsWeb-based software used for the selection of best-fit models of protein evolution.
View all literature mentionsCell line HeLa is a Cancer cell line with a species of origin Homo sapiens
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