Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The group of dominant non-dystrophic myotonias, comprising disorders characterized by clinically similar forms of myogenic muscle stiffness, is genetically inhomogeneous. Dominant myotonia congenita (Thomsen's disease) is linked to CLCN1, the gene encoding the major muscle chloride channel, localized on chromosome 7q35. In contrast, dominant myotonias sensitive to potassium are caused by point mutations in SCN4A on chromosome 17q, the gene for the alpha subunit of the adult skeletal muscle sodium channel. No linkage or molecular genetic data are as yet available on 'myotonia levior' characterized by milder symptoms and later onset of myotonia than in Thomsen's disease, and absence of muscle hypertrophy. We report a CLCN1 Gln-552-Arg substitution for a family with dominant inheritance previously diagnosed to have myotonia levior. Thus, this disorder appears as a variant of Thomsen's disease due to mutations leading to low clinical expressivity. In addition, we report a novel Ile-290-Met CLCN1 mutation for a typical Thomsen pedigree. In another family previously diagnosed as having Thomsen's disease, we unexpectedly found a CLCN1 14 bp deletion known to cause recessive myotonia, and a rare Trp-118-Gly polymorphism.
Hum Mol Genet 1995 Aug
PMID:Myotonia levior is a chloride channel disorder. 758 80

The amiloride-sensitive epithelial sodium channel (ENAC) consists of at least three subunits, alpha, beta, and gamma. Sodium conductance occurs when only the alpha subunit is expressed in Xenopus oocytes, but it is greatly enhanced by coexpression of all three subunits. All three subunits have two transmembrane domains. Whether the amiloride binding site exists in the extracellular portion or a transmembrane domain has not been established. Using reverse transcription-polymerase chain reaction in rat taste tissues, we have identified two alternatively spliced transcripts of ENAC (alpha ENACa and alpha ENACb) with deletions of nucleotides that introduce a premature stop codon and may result in proteins shortened by 199 and 216 amino acids, respectively, at the carboxyl terminus. Genomic Southern blots indicate that a single gene accounts for alpha ENAC and the alternatively spliced variants. Reverse transcription-polymerase chain reaction and RNase protection assays demonstrate that alpha ENACa is expressed to a lesser extent than alpha ENAC in kidney, lung, and taste tissues. alpha ENACa differs from alpha ENAC by a deletion in the second transmembrane domain. Despite this deletion, alpha ENACa expression in transfected human embryonic kidney 293 cells or CV-1 cells augments [3H]phenamil binding. The [3H]phenamil binding of alpha ENACa resembles that of alpha ENAC, being inhibited more potently by phenamil (Kd = 65 nM) than amiloride. Unlike alpha ENAC, expression of alpha ENACa in Xenopus oocytes fails to generate amiloride-sensitive Na+ or Li+ currents. These results suggest that the amiloride binding site resides on the extracellular loop of the alpha subunit of ENAC and not the putative second transmembrane domain, which forms a channel pore. Heterogeneity in alpha ENAC isoforms may contribute to the complexity of multimeric structures and functional variation of ENAC.
Mol Pharmacol 1995 Jun
PMID:Alternatively spliced forms of the alpha subunit of the epithelial sodium channel: distinct sites for amiloride binding and channel pore. 760 52

Although the pattern of expression of various sodium channel alpha- and beta-subunits changes as development proceeds, the mechanisms that control the expression of these subunits are not yet understood. To study the role of nerve growth factor (NGF) in modulating the expression of sodium channel subunits, we used in situ hybridization cytochemistry to examine the distribution of sodium channel alpha- and beta 1-subunit mRNAs in embryonic day 16 (E16) dorsal root ganglia (DRG) neurons cultured in the absence or presence of NGE. At 4 days in vitro in the absence of NGF, sodium channel alpha-subunit II mRNA was expressed at low-to-moderate levels in DRG neurons, but the transcripts for sodium channel alpha-subunits I, III and NaG and beta 1-subunit were not detectable. In the presence of NGF, DRG neurons expressed low-to-moderate levels of sodium channel alpha-I, high levels of alpha-II and low levels of alpha-III; NaG mRNA was not detectable. Sodium channel beta 1 mRNA was up-regulated and was expressed at high levels in DRG neurons in NGF-containing media. These observations demonstrate that the NGF exerts a differential up-regulation of sodium channel alpha- and beta-subunit mRNAs in DRG neurons derived from E16 embryos.
Brain Res Mol Brain Res 1995 May
PMID:Differential up-regulation of sodium channel alpha- and beta 1-subunit mRNAs in cultured embryonic DRG neurons following exposure to NGF. 760 49

The process of stereolithography, which automatically fabricates plastic models from designs created in certain computer-aided design programs, has been applied to the production of accurate plastic molecular models. Atomic coordinates obtained from quantum mechanical calculations and from neutron diffraction data were used to locate spheres in the I-DEAS CAD program with radii proportional to the appropriate van der Waals radii. The sterolithography apparatus was used to build the models using a photosensitive liquid resin, resulting in hard plastic models that accurately represent the computed or experimental input structures. Three examples are given to illustrate how the models can be used to interpret experimental structure-activity data for systems of biological importance or host-guest chemistry: (1) Interpretation of kinetic data for the formation of a stable blocking complex between amiloride analogs and the epithelial sodium channel, (2) interpretation of binding and neural activity data for the interaction of certain amino acids and their analogs at the L-alanine taste receptor of the channel catfish, and (3) interpretation of shape selectivity and rate acceleration in cyclodextrin catalysis using models of the neutron diffraction structure of beta-cyclodextrin and of the transition state for the cleavage of phenyl acetate by the secondary hydroxyl oxygen of beta-cyclodextrin.
J Mol Graph 1995 Apr
PMID:The application of stereolithography to the fabrication of accurate molecular models. 761 88

The Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1) and autoimmune polyglandular disease type I (APECED) have been mapped to human chromosome 21q22.3 by genetic linkage analysis and/or linkage disequilibrium studies. In order to isolate the genes for these disorders, we have constructed BAC contigs in this region and a 14 week trisomy 21 fetal brain cDNA library. A direct cDNA selection technique, modified to permit the recovery 5' and 3' ends of cDNA, was applied to gene identification using the BAC contigs. We have isolated and characterized a novel gene defined by three overlapping but distinct cDNAs of 5, 3, and 3 kb in size all named EHOC-1 (Epilepsy, HOloprosencephaly Candidate-1). This gene maps less than 45 kb centromeric of D21S25, and spans at least 56 kb of genomic DNA. Northern analysis of the 5 kb cDNA revealed that 8, 7.5 and 5.3 kb transcripts are ubiquitously expressed in adult tissues. DNA sequence analysis of the 5 kb cDNA showed a complete coding sequence of 3570 bp that has multiple putative transmembrane domains and has partial homologies to transmembrane proteins including sodium channel proteins. This gene (EHOC-1) is a good candidate for APECED, and particularly for EPM1 because of the location, size, structure and homologies.
Hum Mol Genet 1995 Apr
PMID:Isolation and characterization of a candidate gene for progressive myoclonus epilepsy on 21q22.3. 763 21

We have determined the solution structure of an alpha-toxin, CsE-V, isolated from the venom of the New World scorpion Centruroides sculpturatus Ewing (CsE). This toxin causes spontaneous rhythmic contractions in muscle. Unlike other New World toxins from CsE, this protein exhibits amino acid insertions and deletions at locations similar to Old World toxins and may thus represent a transition protein between the New World and Old World scorpion alpha-toxins. Sequence-specific assignments were made using 600 MHz 1H two-dimensional NMR data. NOESY, PH-COSY and amide-exchange data were used to deduce constraints for molecular modeling calculations. Distance geometry and dynamical simulated annealing calculations were performed to generate a family of 70 structures free of constraint violations. With respect to this family of structures, the energy-minimized average structure had root-mean-square deviations of 0.74 and 1.32 A for backbone and all atoms, respectively (excluding the C-terminal dipeptide, which is disordered). As with other scorpion toxins, the secondary structure of CsE-V consists of an alpha-helix, a three-strand anti-parallel beta-sheet, four beta-turns, and a hydrophobic patch that includes tyrosine residues in herringbone configuration. Unlike the CsE-v3 and -v1 proteins from C. sculpturatus, all of the proline residues were found to be in the trans configuration. The alpha-helix is slightly longer in CsE-V. The overall structure is more similar to the Old World alpha-toxin AaH-II from Androctonus australis Hector (r.m.s.d 1.59 A for backbone atoms of matching residues) than to the New World alpha-toxin CsE-v3 (r.m.s.d. 1.91 A). These structural data on CsE-V add further to our knowledge of the conformational repertoire exhibited by these sodium channel-binding neurotoxins.
J Mol Biol 1995 Apr 28
PMID:Solution structure of an Old World-like neurotoxin from the venom of the New World scorpion Centruroides sculpturatus Ewing. 773 52

It is often suggested that polygenic or environmental factors are responsible for clinical variability between patients with identical mutations. However, most dominant diseases are caused by a change-of-function alteration in the mutant allele's protein product. All patients are heterozygous and presumably express both mutant and normal proteins from the corresponding genes. Thus, a possible molecular mechanism for clinical variability could be the difference in relative levels of mutant vs. normal mRNA in different patients with the same mutation. To investigate this hypothesis, it is necessary to have access to a series of tissue biopsies from many patients with the same mutation causing a clinically variable dominant disease. Human hyperkalemic periodic paralysis (HyperPP) has been shown to be a clinically variable disorder caused by change-of-function mutations of the skeletal muscle sodium channel protein. We recently identified a large (> 50,000) pedigree of affected Quarter Horses sharing the same causative amino acid alteration of the muscle sodium channel protein. The horses like humans show substantial clinical variability. In this report, we developed a fluorescent reverse transcription-polymerase chain reaction assay which quantifies the relative levels of normal and mutant mRNA expression of the horse adult skeletal muscle sodium channel gene in affected Quarter Horses. We found that asymptomatic horses showed more normal sodium channel mRNA, while moderately affected horses showed more mutant mRNA. The ratios of mutant/normal mRNA between these two groups are statistically different, suggesting that severity of HyperPP Quarter Horses may indeed be correlated to the ratio of mutant and normal sodium channel gene expression in skeletal muscle.
Hum Mol Genet 1994 Sep
PMID:Pathophysiology of sodium channelopathies: correlation of normal/mutant mRNA ratios with clinical phenotype in dominantly inherited periodic paralysis. 783 17

Pyrethroids are an important class of insecticides for controlling insect pests, including the German cockroach. Unfortunately, many insects have developed resistance to pyrethroids. One of the most important mechanisms of resistance is kdr (knockdown resistance) which is characterized by neural insensitivity to pyrethroids and DDT. To investigate whether the voltage-dependent sodium channel is involved in kdr-type resistance in the German cockroach, we isolated a 120 bp DNA fragment of the para-homologous sodium channel gene from German cockroaches. Using this fragment as a probe, we identified a restriction fragment length polymorphism (RFLP) of the para-homologous sodium channel gene between susceptible and kdr-type resistant German cockroaches. RFLP analysis of F2 and backcross cockroach populations (total of 331 individuals) showed that all homozygous resistant individuals had a 3.7 kb EcoRI fragment, all homozygous susceptible individuals had a 3.0 kb EcoRI fragment, and all heterozygous individuals had both 3.7 and 3.0 kb fragments. No recombination was detected between the kdr-type resistance locus and the para-homologous sodium channel gene. This suggests that the kdr-type resistance locus and para-homologous sodium channel gene are identical or tightly linked (< 0.2 cM) in German cockroaches. Our results provide strong evidence that modification of para-homologous sodium channels is associated with kdr-type resistance.
Insect Biochem Mol Biol 1994 Jul
PMID:Linkage of kdr-type resistance and the para-homologous sodium channel gene in German cockroaches (Blattella germanica). 791 70

The cellular localization of rat brain sodium channel alpha-subunit mRNAs I, II and III in the central nervous system (CNS) was examined by non-isotope in situ hybridization cytochemistry utilizing two independent sets of isoform-specific RNA probes, one set recognizing sodium channel isoforms in the coding region and the other in the non-coding region of the sodium channel messages. The independent sets of probes demonstrated qualitatively similar patterns of sodium channel mRNA expression. In the hippocampus, sodium channel mRNA I was very weakly expressed in the pyramidal layer and in the granular layer of the dentate gyrus; in contrast, sodium channel mRNA II was strongly expressed by neurons in these regions. Sodium channel mRNA III exhibited low-to-moderate expression in some neurons of the pyramidal layer of the hippocampus and granular layer of the dentate gyrus, and was not detectable in others. In the cerebellum, sodium channel mRNA I was moderately expressed in some Purkinje cells, weakly expressed in scattered cells in the molecular layer and negligibly expressed in the granular layer. Sodium channel mRNA II was strongly expressed in Purkinje and granule cells, and was moderately expressed in some cells in the molecular layer. Sodium channel mRNA III was generally not detectable in the cerebellum. In the spinal cord, motor neurons and scattered neurons throughout the gray matter exhibited moderate-to-strong expression of both sodium channel mRNA I and II. A population of cells in the spinal zone of Lissauer showed heavy expression of mRNA II, but not mRNA I. Sodium channel mRNA III was not detectable in spinal cord neurons. These observations are consistent with a general regional distribution of sodium channel message isoforms, with mRNA II being preferentially expressed in rostral regions of the CNS and mRNA I in caudal regions. However, the results also indicate that different cell types, within a given region, display different patterns of sodium channel mRNA expression. Moreover, these data suggest that individual neurons may express multiple forms of sodium channel mRNA.
Brain Res Mol Brain Res 1994 Mar
PMID:Sodium channel mRNAs I, II and III in the CNS: cell-specific expression. 801 85

The expression of rat brain sodium channel alpha-subunit mRNAs I, II and III and a putative glial cell-specific sodium channel (NaG) mRNA was examined in cultured astrocytes from P-0 rat spinal cord by RNA blot hybridization and by non-isotope in situ hybridization cytochemistry utilizing two independent sets of isoform-specific RNA probes. Sodium channel mRNA I was not detectable in the cultured astrocytes by RNA blot or in situ hybridization. Sodium channel mRNA II showed negligible-to-low levels of expression in flat, fibroblast-like and 'pancake' astrocytes at 4 days in vitro (div), while stellate, process-bearing astrocytes exhibited low-to-moderate levels of mRNA II expression. At 7 div, mRNA II expression ranged from low-to-moderate in flat astrocytes and was moderately high in most process-bearing astrocytes. In RNA blots, a weak band was observed at 9.5 kb. Sodium channel mRNA III expression was negligible in flat astrocytes and was detectable in low-to moderate levels in stellate astrocytes beginning at 4 div; by 7 div, mRNA III was detectable in low levels in flat astrocytes and low-to-moderate levels in stellate astrocytes. RNA blots showed two bands of nearly equal intensity, one at 9.0 kb and one at 7.2 kb. NaG mRNA showed increased expression with time in culture, being detectable in flat and stellate astrocytes at 4 div and becoming very prominent in flat astrocytes at extended times in culture. In RNA blots of cultured astrocytes at 7 div, a strong hybridizing signal with the NaG probe was observed. These observations demonstrate that flat and stellate astrocytes cultured from rat spinal cord express rat brain sodium channel mRNA II and III, and NaG, and suggest that astrocytes in vitro may co-express multiple forms of sodium channel mRNA.
Brain Res Mol Brain Res 1994 May
PMID:Sodium channel mRNAs in cultured spinal cord astrocytes: in situ hybridization in identified cell types. 805 80


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