Disease relevance of Clcn1

• Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy [1].
• Exploring the mammalian neuromuscular system by analysis of mutations: spinal muscular atrophy and myotonia [2].
• Thus it appears that, at the level of the muscle fibre, myotonia and muscular dystrophy attenuate each other [3].
• The detection of the stop codon in the adrmto allele is further indication of the identity of the Clc-1 chloride channel with the adr myotonia gene in the mouse, because a chain termination close to the N terminus would necessarily destroy gene function [4].
• Also, myofibers infected with a recombinant Semliki Forest virus (SFV) expressing myc-tagged ClC-1 showed intracellular localization of the protein [5].

Psychiatry related information on Clcn1

• Myotonic dystrophy (DM) is an autosomal dominant disorder characterized by skeletal muscle wasting, myotonia, cardiac arrhythmia, hyperinsulinaemia, mental retardation and ocular cataracts [6].
• In this study, by means of whole-cell patch-clamp recordings, we examined the effects of taurine on chloride channel receptors in neocortical neurons from early to late postnatal stages, which cover a critical period in cortical circuit formation [7].

High impact information on Clcn1

• Thus the loss of distinct Cl- channels leads to an impairment of transepithelial transport in cystic fibrosis and Bartter's syndrome, to increased muscle excitability in myotonia congenita, to reduced endosomal acidification and impaired endocytosis in Dent's disease, and to impaired extracellular acidification by osteoclasts and osteopetrosis [8].
• We were surprised to find that mice overexpressing a normal DMPK 3' UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology and RNA splicing defects in the absence of detectable nuclear inclusions [9].
• Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia) [10].
• Schwartz-Jampel syndrome (SJS1) is a rare autosomal recessive disorder characterized by permanent myotonia (prolonged failure of muscle relaxation) and skeletal dysplasia, resulting in reduced stature, kyphoscoliosis, bowing of the diaphyses and irregular epiphyses [10].
• CLC-K1 is a kidney-specific chloride channel that mediates transepithelial chloride transport in the thin ascending limb of Henle's loop (tAL) in the inner medulla [11].

Chemical compound and disease context of Clcn1

• Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy [12].
• Here we show that colonization of the lungs by human breast cancer cells is correlated with cell surface expression of the alpha(6)beta(4) integrin and adhesion to human CLCA2 (hCLCA2), a Ca(2+)-sensitive chloride channel protein that is expressed on the endothelial cell luminal surface of pulmonary arteries, arterioles, and venules [13].
• METHODS: The effects of niflumic acid (NA), a relatively specific blocker of calcium-activated chloride channel (CLCA), on goblet cell hyperplasia, eosinophil accumulation, and airway hyperresponsiveness were evaluated after IL-13 instillation into the airways [14].
• The loss of the chloride channel, ClC-5, delays apical iodide efflux and induces a euthyroid goiter in the mouse thyroid gland [15].
• In mice bearing the MDR MCF-7/adr cell xenografts, coadministration of Tet potentiated the antitumour activity of doxorubicin without a significant increase in toxicity [16].

Biological context of Clcn1

• Nevertheless, in +/adr heterozygous, phenotypically wild type (WT) animals, the expression levels of both alleles correspond to the gene dosage [17].
• The results indicate that peak ClC-1 current density at -140 mV is reduced >70% (-48.5 +/- 3.6 and -14.0 +/- 1.6 pA/pF, respectively) and the kinetics of channel deactivation increased in FDB fibers obtained from 18-20- d-old HSA(LR) mice [18].
• Thus, the structural gene for PV, designated Pva, maps to chromosome 15 of the mouse whereas the adr mutation shows no linkage with markers on this chromosome [19].
• MYOTONIA (stiffness and impaired relaxation of skeletal muscle) is a symptom of several diseases caused by repetitive firing of action potentials in muscle membranes [20].
• This conductance is essential for membrane-potential stability, as its block by 9-anthracene-carboxylic acid and other drugs causes myotonia [21].

Anatomical context of Clcn1

• Here, we show that overexpression of Mbnl1 in vivo mediated by transduction of skeletal muscle with a recombinant adeno-associated viral vector rescues disease-associated muscle hyperexcitability, or myotonia, in the HSA(LR) poly(CUG) mouse model for DM [1].
• In the mouse, there is very little ClC-1 mRNA in myotubes, and its concentration increases steeply during postnatal development, suggesting a role of the motor nerve in ClC-1 expression [17].
• Neither effect of denervation was observed in myotonic mice (homozygous for the alleles adr or adrK), suggesting that spontaneous electrical activity of the hyperexcitable sarcolemma may substitute for nerve activity [17].
• Furthermore, electrical myotonia was demonstrated in isolated ADR muscle fibers devoid of nerve endings [22].
• Mutants homozygous for du, mto, spa and tg had virtually normal lipid levels in both the optic and peripheral nerves [23].

Associations of Clcn1 with chemical compounds

• The gene mutation in the mouse, 'arrested development of righting response', adr, causes a defect of chloride conductance of the muscle fibre membrane leading to the symptoms of myotonia [Mehrke, G., Brinkmeier, H. and Jockusch, H. (1988) Muscle & Nerve 11, 440-446] [24].
• In order to study the nature of two other alleles, adrmto and adrK, we have analyzed overlapping Clc-1 cDNA amplification products by the hydroxylamine and osmium tetroxide modification technique and direct sequencing [4].
• Glycolytic, pentose-phosphate shunt and transaminase enzymes in gastrocnemius muscle, liver, heart, and brain of two mouse mutants, 129 J-dy and A2g-adr, with abnormal muscle function [25].
• Alanine and aspartate aminotransferase activities were normal or low in 129 J-dy muscle but increased to approximately 200% in A2G-adr muscle [25].
• The pentose-phosphate shunt enzymes, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, were both greatly increased in the gastrocnemius of 129 J-dy mice, but only the former was slightly increased in A2G-adr muscle [25].

Physical interactions of Clcn1

• To further study the putative gamma-butyrolactone site of the GABAA/chloride channel complex, constrained derivatives of convulsant and anticonvulsant alpha,alpha-disubstituted gamma-butyrolactones (alpha-spirocyclopropyl- and alpha-spirocyclopentyl-gamma-butyrolactones) were synthesized and evaluated biologically [26].

Regulatory relationships of Clcn1

• Chloride channel-2 (ClC-2) is a pH- and voltage-activated chloride channel that is highly expressed in mammalian fetal airway epithelia during the period of maximal fluid secretion [27].
• These results are consistent with murine CFTR being a cAMP-activated chloride channel inhibited by glibenclamide and resistant to DIDS [28].
• Furthermore, the chloride channel blocker picrotoxinin blocked the inhibition of prolactin release elicited by both dopamine and muscimol [29].

Other interactions of Clcn1

• In WT muscle, denervation within 2 days caused a drastic reduction of the ClC-1 mRNA level and at the same time an increase of myogenin and MyoD mRNAs [17].
• Znf9 is normally highly expressed in heart and skeletal muscle, where skeletal muscle chloride channel 1 (Clc1) plays an important role [30].
• To test this hypothesis in vivo, we bred a double mutant mouse that combines two genetic defects: the dystrophin-deficiency of the MDX mouse and the Cl- channel myotonia of the arrested development of righting response (ADR) mouse [31].
• Regulation of the ClC-2 lung epithelial chloride channel by glycosylation of SP1 [27].
• Aldolase and phosphoglycerate kinase activity were markedly reduced in muscle from two mouse mutants, 129 J-dy and A2G-adr, with abnormal muscle development [25].

Analytical, diagnostic and therapeutic context of Clcn1

• No changes in GSL expression were found in the A2G-adr mouse, while muscle of the BL6-wr mouse showed increased intensity of immunofluorescence in stainings with anti-lactosylceramide and anti-GM3(Neu5Ac) antibodies [32].
• Muscle hyperexcitability was attributed to defects in sodium channels and/or to a decrease in chloride conductance (in Becker's myotonia and in genetic animal models) [20].
• The B6MT mouse showed moderate to severe action myotonia, and electromyography revealed myotonic discharge [33].
• Similar myotonic symptoms could be evoked in muscle fibres from 7 day wildtype mice after substitution of the external chloride with impermeant anions or by activators of protein kinase C. The genotypes of 3-day-old mice cannot be inferred from inspection and, thus, were identified by Southern blotting with a ClC-1 probe [34].
• The mouse Clc1/myotonia gene: ETn insertion, a variable AATC repeat, and PCR diagnosis of alleles [35].

References