Novel CLCN1 mutations with unique clinical and electrophysiological consequences

Wu, Fen; Ryan, Aisling; Devaney, Joseph M.; Warnstedt, Maike; Korade, Željka; Poser, Barbara; Escriva, Maria Jose; Pegoraro, Elena; Yee, Audrey S.; Felice, Kevin J.; Giuliani, Michael J.; Mayer, Richard F.; Mongini, Tiziana; Palmucci, L.; Marino, Matthew; Rüdel, Reinhardt; Hoffman, Eric P.; Fahlke, Christoph

doi:10.1093/brain/awf246

Cited by 80 publications

(90 citation statements)

References 39 publications

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“…Early truncating (i.e., nonsense) mutations are thought to exhibit AR inheritance due to loss of the ability of allelic gene products to produce heterodimers [4][5][6] .…”

Section: Letter To the Editormentioning

confidence: 99%

Novel N‐terminal truncating CLCN1 mutation in severe becker disease

et al. 2014

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“…Early truncating (i.e., nonsense) mutations are thought to exhibit AR inheritance due to loss of the ability of allelic gene products to produce heterodimers [4][5][6] .…”

Section: Letter To the Editormentioning

confidence: 99%

Novel N‐terminal truncating CLCN1 mutation in severe becker disease

et al. 2014

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“…To test whether the expression of heterodimeric concatamers supports the formation of homodimers by such a mechanism, we inserted a naturally occurring, disease-causing point mutation, S132C (28), in one of the two subunits. S132C modifies gating properties of ClC-1 in homodimeric S132C hClC-1 and in heterodimeric WT-S132C hClC-1 channels in a different way (Fig.…”

Section: C-g)mentioning

confidence: 99%

The Role of the Carboxyl Terminus in ClC Chloride Channel Function

Hebeisen

Biela

Giese

et al. 2004

Journal of Biological Chemistry

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The human muscle chloride channel ClC-1 has a 398-amino acid carboxyl-terminal domain that resides in the cytoplasm and contains two CBS (cystathionine-␤-synthase) domains. To examine the role of this region, we studied various carboxyl-terminal truncations by heterologous expression in mammalian cells, whole-cell patch clamp recording, and confocal imaging. Channel constructs lacking parts of the distal CBS domain, CBS2, did not produce functional channels, whereas deletion of CBS1 was tolerated. ClC channels are dimeric proteins with two ion conduction pathways (protopores). In heterodimeric channels consisting of one wild type subunit and one subunit in which the carboxyl terminus was completely deleted, only the wild type protopore was functional, indicating that the carboxyl terminus supports the function of the protopore. All carboxylterminal-truncated mutant channels fused to yellow fluorescent protein were translated and the majority inserted into the plasma membrane as revealed by confocal microscopy. Fusion proteins of cyan fluorescent protein linked to various fragments of the carboxyl terminus formed soluble proteins that could be redistributed to the surface membrane through binding to certain truncated channel subunits. Stable binding only occurs between carboxyl-terminal fragments of a single subunit, not between carboxyl termini of different subunits and not between carboxyl-terminal and transmembrane domains. However, an interaction with transmembrane domains can modify the binding properties of particular carboxyl-terminal proteins. Our results demonstrate that the carboxyl terminus of ClC-1 is not necessary for intracellular trafficking but is critical for channel function. Carboxyl termini fold independently and modify individual protopores of the double-barreled channel.ClC channels are found in almost all prokaryotic and in eukaryotic cells. Nine isoforms (ClC-1 to ClC-7, ClC-Ka and ClC-Kb) were shown to be expressed in human tissues and to fulfil a variety of functional roles. ClC-1 is the major muscle chloride channel responsible for the regulation of muscle excitability (1, 2), and ClC-2 is crucial for neuronal chloride homeostasis (3). ClC-Kb is involved in transepithelial NaCl movement in the thick ascending limb of Henle (4), and ClC-3, -5, and -7 are necessary for the pH adjustment of several cell compartments (5-7).Eukaryotic and prokaryotic ClC channels exhibit 18 transmembrane domains (8) followed by cytoplasmic carboxyl termini of variable sequences. The carboxyl-terminal tails of mammalian isoforms contain between 146 and 404 amino acids and exhibit two structurally defined domains, so-called CBS domains (9, 10). The functional importance of the carboxyl terminus is illustrated by disease-causing mutations in ClC-1, -2, -5 and ClC- Kb (3,6,11,12). Moreover, truncations removing parts of the distal cystathionine-␤-synthase (CBS) 1 domain of ClC channels were shown to abolish functional expression in heterologous systems (6,(13)(14)(15)(16). Although co-expression of the complemen...

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“…Others mainly performed in vitro studies for the confirmation of novel mutations in one of these genes. 36,42,43 In the future, such studies should also be done for the eight novel missense mutations detected in our study.…”

mentioning

confidence: 93%

In tandem analysis of CLCN1 and SCN4A greatly enhances mutation detection in families with non-dystrophic myotonia

et al. 2008

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Non-dystrophic myotonias (NDMs) are caused by mutations in CLCN1 or SCN4A. The purpose of the present study was to optimize the genetic characterization of NDM in The Netherlands by analysing CLCN1 and SCN4A in tandem. All Dutch consultant neurologists and the Dutch Patient Association for Neuromuscular Diseases (Vereniging Spierziekten Nederland) were requested to refer patients with an initial diagnosis of NDM for clinical assessment and subsequent genetic analysis over a full year. Based on clinical criteria, sequencing of either CLCN1 or SCN4A was performed. When previously described mutations or novel mutations were identified in the first gene under study, the second gene was not sequenced. If no mutations were detected in the first gene, the second gene was subsequently also analysed. Underlying NDM mutations were explored in 54 families. In total, 20% (8 of 40) of our probands with suspected chloride channel myotonia showed no CLCN1 mutations but subsequent SCN4A screening revealed mutations in all of them. All 14 probands in whom SCN4A was primarily sequenced showed a mutation. In total, CLCN1 mutations were identified in 32 families (59%) and SCN4A in 22 (41%), resulting in a diagnostic yield of 100%. The yield of mutation detection was 93% with three recessive and three sporadic cases not yielding a second mutation. Among these mutations, 13 in CLCN1 and 3 in SCN4A were novel. In conclusion, the current results show that in tandem analysis of CLCN1 and SCN4A affords high-level mutation ascertainment in families with NDM.

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Novel CLCN1 mutations with unique clinical and electrophysiological consequences

Cited by 80 publications

References 39 publications

Novel N‐terminal truncating CLCN1 mutation in severe becker disease

Novel N‐terminal truncating CLCN1 mutation in severe becker disease

The Role of the Carboxyl Terminus in ClC Chloride Channel Function

In tandem analysis of CLCN1 and SCN4A greatly enhances mutation detection in families with non-dystrophic myotonia

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