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Second Transmembrane Domain (second + transmembrane_domain)
Selected AbstractsAutosomal dominant nocturnal frontal lobe epilepsy with a mutation in the CHRNB2 geneEPILEPSIA, Issue 3 2008Fernando Díaz-Otero Summary Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE; MIM 600513) has been associated with mutations in the genes coding for the alfa-4 (CHRNA4), beta-2 (CHRNB2), and alpha-2 (CHRNA2) subunits of the neuronal nicotinic acetylcholine receptor (nAChR) and for the corticotropin-releasing hormone (CRH). A four-generation ADNFLE family with six affected members was identified. All affected members presented the clinical characteristics of ADNFLE. Interictal awake and sleep EEG recordings showed no epileptiform abnormalities. Ictal video-EEG recordings showed focal seizures with frontal lobe semiology. Mutation analysis of the CHRNB2 gene revealed a c.859G>A transition (Val287Met) within the second transmembrane domain, identical to that previously described in a Scottish ADNFLE family. To our knowledge, this is the third family reported presenting a mutation in CHRNB2. The clinical phenotype appears similar to that described with mutations in CHRNA4, suggesting that mutations in these two subunits lead to similar functional alterations of the nAChR. [source] A New Chrna4 Mutation with Low Penetrance in Nocturnal Frontal Lobe EpilepsyEPILEPSIA, Issue 7 2003Tobias Leniger Summary: Purpose: To identify and characterize the mutation(s) causing nocturnal frontal lobe epilepsy in a German extended family. Methods: Neuronal nicotinic acetylcholine receptor (nAChR) subunit genes were screened by direct sequencing. Once a CHRNA4 mutation was identified, its biophysical and pharmacologic properties were characterized by expression experiments in Xenopus oocytes. Results: We report a new CHRNA4 mutation, causing a ,4-T265I amino acid exchange at the extracellular end of the second transmembrane domain (TM). Functional studies of ,4-T265I revealed an increased ACh sensitivity of the mutated receptors. ,4-T265I is associated with an unusual low penetrance of the epilepsy phenotype. Sequencing of the TM1-TM3 parts of the 1 known nAChR subunits did not support a two-locus model involving a second nAChR sequence variation. Conclusions: nAChR mutations found in familial epilepsy are not always associated with an autosomal dominant mode of inheritance. ,4-T265I is the first nAChR allele showing a markedly reduced penetrance consistent with a major gene effect. The low penetrance of the mutation is probably caused by unknown genetic or environmental factors or both. [source] A Putative Alternatively Spliced Variant of the P2X1 Purinoreceptor in Human BladderEXPERIMENTAL PHYSIOLOGY, Issue 4 2000L. A. Hardy Activation of purinergic P2X receptors, putatively P2X1, may be important in the initiation of contraction in human detrusor. Purinergic transmission may be more important in muscle taken from patients with bladder instability. In this study the presence of the P2X1 receptor subtype was confirmed using RT-PCR. In addition, the results indicate, at the mRNA level, the presence of a splice variant of P2X1 that is lacking part of the second transmembrane domain. It is therefore possible that human bladder expresses multiple isoforms of the P2X1 receptor which may be potential sites for modifying or regulating putative purinergic activation of the human bladder. [source] Molecular determinants of ginkgolide binding in the glycine receptor poreJOURNAL OF NEUROCHEMISTRY, Issue 2 2006Rebecca Hawthorne Abstract Ginkgolides are potent blockers of the glycine receptor Cl, channel (GlyR) pore. We sought to identify their binding sites by comparing the effects of ginkgolides A, B and C and bilobalide on ,1, ,2, ,1, and ,2, GlyRs. Bilobalide sensitivity was drastically reduced by incorporation of the , subunit. In contrast, the sensitivities to ginkgolides B and C were enhanced by , subunit expression. However, ginkgolide A sensitivity was increased in the ,2, GlyR relative to the ,2 GlyR but not in the ,1, GlyR relative to the ,1 GlyR. We hypothesised that the subunit-specific differences were mediated by residue differences at the second transmembrane domain 2, and 6, pore-lining positions. The increased ginkgolide A sensitivity of the ,2, GlyR was transferred to the ,1, GlyR by the G2,A (,1 to ,2 subunit) substitution. In addition, the ,1 subunit T6,F mutation abolished inhibition by all ginkgolides. As the ginkgolides share closely related structures, their molecular interactions with pore-lining residues were amenable to mutant cycle analysis. This identified an interaction between the variable R2 position of the ginkgolides and the 2, residues of both ,1 and , subunits. These findings provide strong evidence for ginkgolides binding at the 2, pore-lining position. [source] Stoichiometry of a pore mutation that abolishes picrotoxin-mediated antagonism of the GABAA receptorTHE JOURNAL OF PHYSIOLOGY, Issue 2 2006Anna Sedelnikova Picrotoxin, a potent antagonist of the inhibitory central nervous system GABAA and glycine receptors, is believed to interact with residues that line the central ion pore. These pore-lining residues are in the second transmembrane domain (TM2) of each of the five constituent subunits. One of these amino acids, a threonine at the 6, location, when mutated to phenylalanine, abolishes picrotoxin sensitivity. It has been suggested that this threonine, via hydrogen bonding, directly interacts with the picrotoxin molecule. We previously demonstrated that this mutation, in the ,, , or , subunit, can impart picrotoxin resistance to the GABA receptor. Since the functional pentameric GABA receptor contains two , subunits, two , subunits and one , subunit, it is not clear how many , and , subunits must carry this mutation to impart the resistant phenotype. In this study, by coexpression of mutant , or , subunits with their wild-type counterparts in various defined ratios, we demonstrate that any single subunit carrying the 6, mutation imparts picrotoxin resistance. Implications of this finding in terms of the mechanism of antagonism are considered. [source] A novel homozygous mutation in the second transmembrane domain of the gonadotrophin releasing hormone receptor geneCLINICAL ENDOCRINOLOGY, Issue 4 2001D. Söderlund BACKGROUND and OBJECTIVE Mutations in the GnRH receptor (GnRH-R) gene cause hypogonadotrophic hypogonadism. Here, we present the molecular studies of the GnRH-R gene in three families with isolated hypogonadotrophic hypogonadism. PATIENTS Three unrelated families, with at least two members diagnosed with isolated hypogonadotrophic hypogonadism were included. MEASUREMENTS DNA sequencing was performed after polymerase chain reaction amplification of each of the three exons of the gene. RESULTS A novel homozygous missense mutation, at nucleotide 268, turning glutamic acid into lysine, located at the second transmembrane domain of the GnRH-R gene was found in two patients pertaining to one of the families studied. Both parents and an unaffected brother were heterozygous carriers of one mutant allele, an unaffected sister was homozygote wild type. In the other two affected families no mutations were found in the GnRH-R gene. CONCLUSIONS This constitutes the first description of an spontaneous mutation located at the second transmembrane domain (Glu90Lys) of the GnRH-R, indicating that the integrity of glutamic acid at this position is crucial for receptor function. Also this report, complementing others, demonstrates that mutations are distributed throughout the GnRH-R gene and that as in the only other homozygous mutation previously described, affected patients present a complete form of hypogonadotrophic hypogonadism. Due to the fact that apparently consanguinity was present in our affected family, we presume that the mutation derived from a common ancestor, by a founder gene effect. [source] | |||||||||||||