Disease relevance of CACNA1S

• Eleven of 36 families with hypokalemic periodic paralysis (hypoPP) harbored mutations in the skeletal muscle calcium channel gene (CACNA1S) [1].
• Identification of the Arg1086His mutation in the alpha subunit of the voltage-dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia [2].
• Exclusion of linkage of the RYR1, CACNA1S, and ATP2A1 genes to recurrent exertional rhabdomyolysis in Thoroughbreds [3].
• Hypokalaemic periodic paralysis (hypoPP) is a dominantly inherited muscle disorder characterized by episodes of flaccid weakness [4].
• Hypokalaemic periodic paralysis (hypoPP) is an autosomal dominant muscle disorder characterized by episodic attacks of muscle weakness associated with a decrease in blood potassium levels [5].

High impact information on CACNA1S

• Using an intragenic microsatellite, we also demonstrate that the gene encoding the muscle DHP-sensitive calcium channel alpha 1 subunit (CACNL1A3) maps to the same region, sharing a 5 centiMorgan (cM) interval with the HypoPP locus [6].
• Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant disorder belonging to a group of muscle diseases involving the abnormal function of ion channels [7].
• Subsequently, deleterious mutations in the voltage-sensor segment S4 were found, establishing the dihydropyridine receptor CACNL1A3 as the causative gene for hypoPP [7].
• We recently localized the hypoPP locus (hypoPP1) to chromosome 1q31-32, in an interval where the alpha 1 subunit of the dihydropyridine receptor calcium channel (CACNL1A3) also maps [7].
• Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families [7].

Chemical compound and disease context of CACNA1S

• OBJECTIVE: To identify the cause of hypokalemic periodic paralysis (HOKPP) in a family whose disease is not caused by a mutation in the dihydropyridine-sensitive (DHP) receptor alpha1-subunit gene (CACNA1S) [8].
• In the present work, we investigated the mechanism of action of acetazolamide in the K-deficient diet rat, an animal model of human hypokalemic periodic paralysis (hypoPP) [9].
• In three families with hypokalemic periodic paralysis (HOPP) we have confirmed the presence of a missense mutation (arginine 528 to histidine) within the gene CACNL1A3 encoding the alpha 1 subunit of the L-type, voltage-sensitive calcium channel [10].

Biological context of CACNA1S

• This study identifies a novel Arg528Gly mutation in the CACNA1S gene that causes HypoPP in a Chinese family, expands the spectrum of mutations causing HypoPP, and demonstrates a gender difference in the penetrance of the disease [11].
• Linkage analysis showed that the causative mutation in the family is linked to the CACNA1S gene with a LOD score of 6 [11].
• One of these locates to chromosome 1q, the site of a candidate gene, CACNL1A3, encoding the alpha-subunit of the dihydropyridine receptor [12].
• RESULTS: Analysis of the RYR1, CACNA1S, and ATP2A1 microsatellites excluded a link between those markers and the RER trait [3].
• In light of the reported genetic heterogeneity for the disorder and the recent introduction of DNA testing guidelines for the trait, we have assessed the role of the CACNA1S gene in MH susceptibility in UK patients [13].

Anatomical context of CACNA1S

• In contrast, vacuoles were predominant in muscles from hypoPP patients carrying CACNL1A3 mutations [5].
• Oligonucleotides based on this sequence were used in a polymerase chain reaction to amplify specifically the human gene in human-rodent somatic cell hybrids, allowing the assignment of CACNL1A3 to chromosome 1 [14].
• METHODS: We used 2-dimensional gel electrophoresis/mass spectrometry to compare the cerebrospinal fluid proteome of patients with mutation-confirmed CACH/VWM with that of unaffected controls [15].
• Only two of five cases of locally invasive tumor demonstrated seminal vesicles expression for MHS-5 [16].
• Assay systems employing the MHS-5 monoclonal may be useful for identification of semen in sexual-assault casework [17].

Associations of CACNA1S with chemical compounds

• We identified four novel polymorphisms in the CACNA1S gene that encodes the alpha1-subunit of the dihydropyridine receptor [18].
• CONCLUSIONS: The first arginine in DII/S4 and in DIV/S4 within the skeletal muscle sodium channel and the L-type calcium channel genie CACNA1S appear to be critical for normal function [8].
• Some remarkable clinical features were observed in a large hypoPP family carrying an SCN4A mutation: a complete penetrance in men and women, an early age at onset, postcritic myalgias and an increased number and severity of attacks induced by acetazolamide [5].
• Human seminal vesicle was fixed by immersion in combinations of glutaraldehyde and paraformaldehyde and embedded in Araldite or LR Gold. Both the guinea pig polyclonal antibody and the murine monoclonal antibody MHS-5 were employed to localize SVSA in human seminal vesicle by immunoelectron microscopy using Protein-A gold complexes [19].
• Evaluation of toluidine blue-stained, semithin sections of white matter from CACH patients disclosed unusual cells with "foamy" cytoplasm, small round nuclei and fine chromatin [20].

Other interactions of CACNA1S

• In one family, a compound heterozygous patient harboring a RYR1 mutation and a CACNA1S mutation was identified [21].
• Mutations of the CACNA1S gene were screened using polymerase chain reaction-based restriction analysis [22].
• We report the clinical features of, and the molecular study performed on, a Spanish family with essential tremor (ET), late onset epilepsy and autosomal dominant hypokalemic periodic paralysis (hypoPP) [23].

Analytical, diagnostic and therapeutic context of CACNA1S

• Mapping CACNA1S to chromosome 10 in swine using radiation hybrid mapping [24].
• Refined localization of the alpha 1-subunit of the skeletal muscle L-type voltage-dependent calcium channel (CACNL1A3) to human chromosome 1q32 by in situ hybridization [25].
• Western blots of ejaculates allowed to liquefy for 5 min demonstrated the MHS-5 epitope to be located on peptides of a wide range of molecular masses from 69 to 8 kDa [17].
• Using the MHS-5 monoclonal, an enzyme-linked immunosorbent assay (ELISA) was developed sensitive to 1 ng of seminal protein [17].
• The SV-specific protein (SVSP), MHS-5, was present in the control group but was not found in any of the seven samples from azoospermic men with proven agenesis of SV and VD [26].

References