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New immunohistochemical method for improved myotonia and chloride channel mutation diagnostics.

ABSTRACT: OBJECTIVE: The objective of this study was to validate the immunohistochemical assay for the diagnosis of nondystrophic myotonia and to provide full clarification of clinical disease to patients in whom basic genetic testing has failed to do so. METHODS: An immunohistochemical assay of sarcolemmal chloride channel abundance using 2 different ClC1-specific antibodies. RESULTS: This method led to the identification of new mutations, to the reclassification of W118G in CLCN1 as a moderately pathogenic mutation, and to confirmation of recessive (Becker) myotonia congenita in cases when only one recessive CLCN1 mutation had been identified by genetic testing. CONCLUSIONS: We have developed a robust immunohistochemical assay that can detect loss of sarcolemmal ClC-1 protein on muscle sections. This in combination with gene sequencing is a powerful approach to achieving a final diagnosis of nondystrophic myotonia.

SUBMITTER: Raheem O

PROVIDER: S-EPMC3570820 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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New immunohistochemical method for improved myotonia and chloride channel mutation diagnostics.

Raheem Olayinka O Penttilä Sini S Suominen Tiina T Kaakinen Mika M Burge James J Haworth Andrea A Sud Richa R Schorge Stephanie S Haapasalo Hannu H Sandell Satu S Metsikkö Kalervo K Hanna Michael M Udd Bjarne B

Neurology 20121114 22

<h4>Objective</h4>The objective of this study was to validate the immunohistochemical assay for the diagnosis of nondystrophic myotonia and to provide full clarification of clinical disease to patients in whom basic genetic testing has failed to do so.<h4>Methods</h4>An immunohistochemical assay of sarcolemmal chloride channel abundance using 2 different ClC1-specific antibodies.<h4>Results</h4>This method led to the identification of new mutations, to the reclassification of W118G in CLCN1 as a ...[more]

PMID: 23152584

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Project description:The voltage-dependent ClC-1 chloride channel, whose open probability increases with membrane potential depolarization, belongs to the superfamily of CLC channels/transporters. ClC-1 is almost exclusively expressed in skeletal muscles and is essential for stabilizing the excitability of muscle membranes. Elucidation of the molecular structures of human ClC-1 and several CLC homologs provides important insight to the gating and ion permeation mechanisms of this chloride channel. Mutations in the human CLCN1 gene, which encodes the ClC-1 channel, are associated with a hereditary skeletal muscle disease, myotonia congenita. Most disease-causing CLCN1 mutations lead to loss-of-function phenotypes in the ClC-1 channel and thus increase membrane excitability in skeletal muscles, consequently manifesting as delayed relaxations following voluntary muscle contractions in myotonic subjects. The inheritance pattern of myotonia congenita can be autosomal dominant (Thomsen type) or recessive (Becker type). To date over 200 myotonia-associated ClC-1 mutations have been identified, which are scattered throughout the entire protein sequence. The dominant inheritance pattern of some myotonia mutations may be explained by a dominant-negative effect on ClC-1 channel gating. For many other myotonia mutations, however, no clear relationship can be established between the inheritance pattern and the location of the mutation in the ClC-1 protein. Emerging evidence indicates that the effects of some mutations may entail impaired ClC-1 protein homeostasis (proteostasis). Proteostasis of membrane proteins comprises of biogenesis at the endoplasmic reticulum (ER), trafficking to the surface membrane, and protein turn-over at the plasma membrane. Maintenance of proteostasis requires the coordination of a wide variety of different molecular chaperones and protein quality control factors. A number of regulatory molecules have recently been shown to contribute to post-translational modifications of ClC-1 and play critical roles in the ER quality control, membrane trafficking, and peripheral quality control of this chloride channel. Further illumination of the mechanisms of ClC-1 proteostasis network will enhance our understanding of the molecular pathophysiology of myotonia congenita, and may also bring to light novel therapeutic targets for skeletal muscle dysfunction caused by myotonia and other pathological conditions.

Dataset Information

New immunohistochemical method for improved myotonia and chloride channel mutation diagnostics.

Publications

New immunohistochemical method for improved myotonia and chloride channel mutation diagnostics.

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