A missense mutation in the skeletal muscle chloride channel 1 (CLCN1) as candidate causal mutation for congenital myotonia in a New Forest pony

Wijnberg, Inge D.; Owczarek‐Lipska, Marta; Sacchetto, Roberta; Mascarello, Francesco; Pascoli, Francesco; Grünberg, Walter; Kolk, Johannes H. van der; Drögemüller, Cord

doi:10.1016/j.nmd.2011.10.001

Cited by 34 publications

(15 citation statements)

References 23 publications

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“…Myotonic pigs were all homozygous recessive for the deletion, whereas their progenitors were heterozygous, and all unrelated, non-myotonic pigs were homozygous “wild type.” A previous study investigating Hereditary Myotonia in cats associated the disease to the absence of exons 15 and 16 in the CLCN1 gene due to a defective donor splicing site 21 . In horses 19 , the disease has been associated with single nucleotide polymorphisms (SNPs) in the same genomic region that was deleted in myotonic pigs. Moreover, at least six other distinct polymorphisms in the genomic region between introns 14 and 17 have been associated with Hereditary Myotonia in humans 41–44 .…”

Section: Discussionmentioning

confidence: 99%

“…Hereditary Myotonia has extensively been reported in humans 7–13 , and it has been associated with more than 200 different mutations affecting the CLCN1 gene 14 . This disease has also been associated with mutations in the CLCN1 gene in rats 15 , goats 16 , dogs 17,18 , horses 19 , buffalo 20 , cats 21 , and sheep 22 . It is clinically characterized by muscle stiffness after stimuli, muscle hypertrophy (mainly observed in the epaxial and appendicular muscles), and warm-up effect 7–13,15–21 .…”

Section: Introductionmentioning

confidence: 99%

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A large intragenic deletion in the CLCN1 gene causes Hereditary Myotonia in pigs

Araújo

Oliveira

Barbosa

et al. 2019

Sci Rep

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Mutations in the CLCN1 gene are the primary cause of non-dystrophic Hereditary Myotonia in several animal species. However, there are no reports of Hereditary Myotonia in pigs to date. Therefore, the objective of the present study was to characterize the clinical and molecular findings of Hereditary Myotonia in an inbred pedigree. The clinical, electromyographic, histopathological, and molecular findings were evaluated. Clinically affected pigs presented non-dystrophic recessive Hereditary Myotonia. Nucleotide sequence analysis of the entire coding region of the CLCN1 gene revealed the absence of the exons 15 and 16 in myotonic animals. Analysis of the genomic region flanking the deletion unveiled a large intragenic deletion of 4,165 nucleotides. Interestingly, non-related, non-myotonic pigs expressed transcriptional levels of an alternate transcript (i.e., X2) that was identical to the deleted X1 transcript of myotonic pigs. All myotonic pigs and their progenitors were homozygous recessive and heterozygous, respectively, for the 4,165-nucleotide deletion. This is the first study reporting Hereditary Myotonia in pigs and characterizing its clinical and molecular findings. Moreover, to the best of our knowledge, Hereditary Myotonia has never been associated with a genomic deletion in the CLCN1 gene in any other species.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A large intragenic deletion in the CLCN1 gene causes Hereditary Myotonia in pigs

Araújo

Oliveira

Barbosa

et al. 2019

Sci Rep

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“…Different degrees of myotonic symptoms can be reported among family members with identical ClC-1 mutations and among different families ( Colding-Jørgensen, 2005 ). Chloride channel myotonia also occurs in animals, including goat, mouse, dog, cat, poney, and water buffalo ( Figure 2 ; Steinmeyer et al, 1991b ; Rhodes et al, 1999 ; Wijnberg et al, 2012 ; Borges et al, 2013 ; Gandolfi et al, 2014 ). The study of myotonia in goats and mice proved to be decisive to the understanding of the pathomechanism, and eventually allowed the cloning of ClC-1 channel.…”

Section: Genetic Diseases Associated To Clc-1mentioning

confidence: 99%

ClC-1 chloride channels: state-of-the-art research and future challenges

Imbrici

Altamura

Pessia

et al. 2015

Front. Cell. Neurosci.

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The voltage-dependent ClC-1 chloride channel belongs to the CLC channel/transporter family. It is a homodimer comprising two individual pores which can operate independently or simultaneously according to two gating modes, the fast and the slow gate of the channel. ClC-1 is preferentially expressed in the skeletal muscle fibers where the presence of an efficient Cl- homeostasis is crucial for the correct membrane repolarization and propagation of action potential. As a consequence, mutations in the CLCN1 gene cause dominant and recessive forms of myotonia congenita (MC), a rare skeletal muscle channelopathy caused by abnormal membrane excitation, and clinically characterized by muscle stiffness and various degrees of transitory weakness. Elucidation of the mechanistic link between the genetic defects and the disease pathogenesis is still incomplete and, at this time, there is no specific treatment for MC. Still controversial is the subcellular localization pattern of ClC-1 channels in skeletal muscle as well as its modulation by some intracellular factors. The expression of ClC-1 in other tissues such as in brain and heart and the possible assembly of ClC-1/ClC-2 heterodimers further expand the physiological properties of ClC-1 and its involvement in diseases. A recent de novo CLCN1 truncation mutation in a patient with generalized epilepsy indeed postulates an unexpected role of this channel in the control of neuronal network excitability. This review summarizes the most relevant and state-of-the-art research on ClC-1 chloride channels physiology and associated diseases.

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“…The non-dystrophic myotonias thus far have been shown to only involve the muscle system, whereas the dystrophic myotonias exhibit multisystem involvement concurrent with additional muscle weakness. Genes involved in Mc are the muscle voltage-gated sodium and chloride channel genes SCN4A ("Dinucleotide repeat polymorphisms at the SCN4A locus suggest allelic heterogeneity of hyperkalemic periodic paralysis and paramyotonia congenita," 1992; Du et al, 2012;Ruscák, 1997;Shirakawa, Sakai, Kitagawa, Hori, & Hirose, 2002) and CLCN1 (Bernard, Poulin, Puymirat, Sternberg, & Shevell, 2008;Grunnet et al, 2003;Wijnberg et al, 2012;Zhang, Bendahhou, Sanguinetti, & Ptácek, 2000), the Myotonic dystrophy protein kinase (DMPK) gene (Meola & Cardani, 2014), and the CCHC-type zinc finger, nucleic acid binding protein gene CNBP (Meola, 2013;Sun et al, 2011). In most forms of MD, membrane damage occurs after prolonged muscle contraction (Blake, Weir, Newey, & Davies, 2002;Petrof, Shrager, Stedman, Kelly, & Sweeney, 1993), which causes a delayed relaxation of the muscles (Beck, Fahlke, & George, 1996).…”

Section: Significance Of the Problemmentioning

confidence: 99%

Characterization of the TRPC3 Gene in Myotonic Goats: Further Insight Into Myotonia congenita and Muscular Dystrophy

Corley¹,

Caviness²

2014

JMBR

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Myotonia congenita (Mc) is a muscle disorder seen in both Myotonic goats and humans, caused by mutations in the chloride ion channel gene (CLCN1). Calcium signaling has been coupled to the function of the CLCN1, but this interaction is not well understood, as individuals with Mc do not experience muscular dystrophy (MD). Over expression of the Transient Receptor Cation Channel 3 (TRPC3), a protein responsible for calcium influx and muscle contraction causes an elevation in calcium which results in a phenotype of MD. Evaluation of the TRPC3 gene in Myotonic goats has not been conducted. Therefore the objective of this experiment was to evaluate gene expression of the TRPC3 gene in Myotonic vs. Spanish goats (control). Total RNA was isolated from whole blood samples. Cross species primers were designed from the human, bovine, and mouse TRPC3 cDNA alignments. The goat partial TRPC3 gene showed 98%, 92% and 91%, and 100%, 98%, and 98% nucleotide and amino acid sequence homology to the bovine, human and mouse TRPC3 genes respectively. Quantitative Real Time PCR showed that gene expression of TRPC3 was 77% higher (P<0.05) in Myotonic than Non-Myotonic (Spanish) goats. Male Myotonic goats expressed 67% higher levels (P<0.05) of TRPC3 than females. The TRPC3 gene expression was 90% higher (P<0.05) in Myotonic goats older than 4 years of age. These data indicate that the TRPC3 gene is a potential biomarker to further study Myotonia congenita in Myotonic goats and the interrelationship of the mechanism of calcium signaling in human Mc and MD.

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A missense mutation in the skeletal muscle chloride channel 1 (CLCN1) as candidate causal mutation for congenital myotonia in a New Forest pony

Cited by 34 publications

References 23 publications

A large intragenic deletion in the CLCN1 gene causes Hereditary Myotonia in pigs

A large intragenic deletion in the CLCN1 gene causes Hereditary Myotonia in pigs

ClC-1 chloride channels: state-of-the-art research and future challenges

Characterization of the TRPC3 Gene in Myotonic Goats: Further Insight Into Myotonia congenita and Muscular Dystrophy

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