Mapping of multiple subunits of the neuronal nicotinic acetylcholine receptor to chromosome 15 in man and chromosome 9 in mouse

Eng, Christine M.; Kozak, Christine A.; Beaudet, Arthur L.; Zoghbi, Huda Y.

doi:10.1016/0888-7543(91)90253-b

Cited by 36 publications

(12 citation statements)

References 20 publications

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“…The ␣3-, ␣5-, and ␤4-nAChR subunit genes are localized in a cluster designated as Chrnb4/Chrna3/Chrna5 on mouse chromosome 9 (5,19). The evolutionary conserved organization of this cluster, the ability of ␣3-, ␣5-, and ␤4-subunits to form a functional receptor, and their overlapping expression in the brain (17,49,60,62) suggested that these three genes share common temporal and spatial transcriptional regulatory mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…They did, however, express the ␣3-subunit gene, which is localized between the ␣5 and the ␤4 genes in the Chrnb4/Chrna3/Chrna5 gene cluster (5) on mouse chromosome 9 (19) (Fig. 1B).…”

Section: Double-null Mutants With ␣5-and ␤4-nachr Subunits Deficiencimentioning

confidence: 99%

“…Targeting deletions of the individual ␣5-and ␤4-nAChR subunit genes in mice were previously described (48,65). Since the ␣5-and the ␤4-nAChR subunit genes are localized within a gene cluster of about 70 kb length on mouse chromosome 9 (5,19), it was not possible to generate double ␣5-and ␤4-deficient mice via breeding of the individual mutants. Therefore, mice with null mutations of both subunits were generated as follows.…”

Section: Generation Of Double-null Mutant Mice With Deficiency In Botmentioning

confidence: 99%

“…Based on the linkage studies results, the localization of the ␤4-nAChR subunit in a gene cluster with the ␣5-and ␣3-subunits (5,19), and the coassembly of these subunits in Xenopus oocytes (27), we hypothesized that the ␤4-nAChR subunit may also play a role in nicotine-induced seizures. To test this possibility, the sensitivity to nicotine-induced seizures was compared between ␤4 null mice, wild-type mice, and mice lacking the ␣5-subunit.…”

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Mice lacking neuronal nicotinic acetylcholine receptor β4-subunit and mice lacking both α5- and β4-subunits are highly resistant to nicotine-induced seizures

Kedmi

Beaudet

Orr-Urtreger

2004

Physiological Genomics

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Kedmi, Merav, Arthur L. Beaudet, and Avi Orr-Urtreger. Mice lacking neuronal nicotinic acetylcholine receptor ␤4-subunit and mice lacking both ␣5-and ␤4-subunits are highly resistant to nicotineinduced seizures. Physiol Genomics 17: 221-229, 2004. First published March 2, 2004 10.1152/physiolgenomics.00202.2003.-Nicotine, the main addictive component of tobacco, evokes a wide range of dose-dependent behaviors in rodents, and when administrated in high doses, it can induce clonic-tonic seizures. Nicotine acts through the nicotinic acetylcholine receptors (nAChRs). Mutations in the human ␣4-and the ␤2-nAChR subunit genes cause autosomal dominant nocturnal frontal lobe epilepsy. Using transgenic mice with mutations in nAChR subunits, it was demonstrated previously that the ␣4-, ␣5-, and ␣7-subunits are involved in nicotine-induced seizures. To examine the possibility that the ␤4-subunit is also involved in this phenotype, we tested mice with homozygous ␤4-subunit deficiency. The ␤4 null mice were remarkably resistant to nicotine-induced seizures compared with wild-type and ␣5 null mice. We also generated mice with double deficiency of both ␣5-and ␤4-nAChR subunits and demonstrated that they were more resistant to nicotine's convulsant effect than either the ␣5 or the ␤4 single mutant mice. In addition, the single ␣5 mutants and the double ␣5␤4-deficient mice exhibited a significantly shorter latency time to seizure than that of the wild-type mice. Our results thus show that ␤4-containing nAChRs have a crucial role in the pathogenesis of nicotine-induced seizures. Furthermore, by comparing multiple mutant mice with single and double subunit deficiency, we suggest that nicotinic receptors containing either ␣5-or ␤4-subunits are involved in nicotine-induced seizures and that receptors containing both subunits are likely to contribute to this phenomena as well. However, the ␣5-subunit, but not the ␤4-subunit, regulates the rate of response to high doses of nicotine.neuronal nicotinic acetylcholine receptor ␣5-and ␤4-subunits; knockout mice NICOTINE ACTS THROUGH THE nicotinic acetylcholine receptors (nAChRs) and can be toxic in high doses in mice, inducing tremors, seizures, and even death (41). The nAChRs are allosteric membrane proteins that belong to a large family of ligand-gated ion channels. Each receptor is composed of a combination of five subunits. To date, 12 neuronal subunits (␣2-␣10 and ␤2-␤4) have been identified (reviewed in Ref. 29). They are widely distributed in the central and peripheral nervous systems and are also expressed in nonneuronal cells (11,14,23,30,37).In humans, nAChRs are associated with a number of pathological conditions, including epilepsy (reviewed in Ref. 35). Mutations in the ␣4-and ␤2-subunit genes were associated with familial cases of autosomal dominant nocturnal frontal lobe epilepsy (15, 45, 52-54). In addition, genetic linkage was found between juvenile myoclonic epilepsy and the chromosomal region encompassing the ␣7-subunit gene (18).In mice, a genetic linkage was shown betw...

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Section: Discussionmentioning

confidence: 99%

“…They did, however, express the ␣3-subunit gene, which is localized between the ␣5 and the ␤4 genes in the Chrnb4/Chrna3/Chrna5 gene cluster (5) on mouse chromosome 9 (19) (Fig. 1B).…”

Section: Double-null Mutants With ␣5-and ␤4-nachr Subunits Deficiencimentioning

confidence: 99%

Section: Generation Of Double-null Mutant Mice With Deficiency In Botmentioning

confidence: 99%

mentioning

confidence: 99%

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Mice lacking neuronal nicotinic acetylcholine receptor β4-subunit and mice lacking both α5- and β4-subunits are highly resistant to nicotine-induced seizures

Kedmi

Beaudet

Orr-Urtreger

2004

Physiological Genomics

Self Cite

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“…Eleven subunits of the nAChR have been identified. Each of the subunit proteins is encoded by a distinct gene, and sequences have been determined for nine human subunit cDNAs (Anand and Lindstrom 1990;Elliott et al 1996;Groot-Kormelink and Luyten 1997), and cDNA probes have been used to map the location of eight of the genes on chromosomes (Orr-Urtreger et al 1995;Eng et al 1991;Anand and Lindstrom 1992). The genomic structure has been determined only for the ␣7 subunit (Gault et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Genomic organization and mapping of the human and mouse neuronal β2-nicotinic acetylcholine receptor genes

et al. 1999

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Abstract. As a first step in determining whether there are polymorphisms in the nicotinic acetylcholine receptor (nAChR) genes that are associated with nicotine addiction, we isolated genomic clones of the ␤2-nAChR genes from human and mouse BAC libraries. Although cDNA sequences were available for the human gene, only the promoter sequence had been reported for the mouse gene. We determined the genomic structures by sequencing 12 kb of the human gene and over 7 kb of the mouse gene. While the sizes of exons in the mouse and human genes are the same, the introns differ in size. Both promoters have a high GC content (60-80%) proximal to the AUG and share a neural-restrictive silencer element (NRSE), but overall sequence identity is only 72%. Using a 6-Mb YAC contig of Chr 1, we mapped the human ␤2-nAChR gene, CHRNB2, to 1q21.3 with the order of markers cen, FLG, IVL, LOR, CHRNB2, tel. The mouse gene, Acrb2, had previously been mapped to Chr 3 in a region orthologous to human Chr 1. We refined mapping of the mouse gene and other markers on a radiation hybrid panel of Chr 3 and found the order cen, Acrb2, Lor, Iv1, Flg, tel. Our results indicate that this cluster of markers on human Chr 1 is inverted with respect to its orientation on the chromosome compared with markers in the orthologous region of mouse Chr 3.

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Novel CHRNA3 variants identified in a patient with bladder dysfunction, dysautonomia, and gastrointestinal dysmotility

Anand,

Hildebrandt,

Shenoy

et al. 2024

American J of Med Genetics Pt A

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Congenital anomalies of the kidney and urinary tract (CAKUT) are estimated to be responsible for 20%–50% of congenital anomalies and are also a leading etiology of early‐onset renal disease. Primary CAKUT are caused by genetic factors that impair proper in‐utero genitourinary tract development and secondary CAKUT result from the influence of environmental factors. The CHRNA3 gene, which encodes the Alpha‐3 subunit of the nicotinic acetylcholine receptor, is hypothesized to be associated with Megacystis‐microcolon‐intestinal hyperperistalsis syndrome. More recently, pathogenic variants in CHRNA3 have been identified in individuals with CAKUT as well as individuals with panautonomic failure. Here we present a patient with neurogenic bladder, vesicoureteral reflux, mydriasis, and gastrointestinal dysmotility found to have novel compound heterozygous variants in CHRNA3. These findings support the consideration of CHRNA3 disruption in the differential for CAKUT with dysautonomia and gastrointestinal dysmotility.

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Mapping of multiple subunits of the neuronal nicotinic acetylcholine receptor to chromosome 15 in man and chromosome 9 in mouse

Cited by 36 publications

References 20 publications

Mice lacking neuronal nicotinic acetylcholine receptor β4-subunit and mice lacking both α5- and β4-subunits are highly resistant to nicotine-induced seizures

Mice lacking neuronal nicotinic acetylcholine receptor β4-subunit and mice lacking both α5- and β4-subunits are highly resistant to nicotine-induced seizures

Genomic organization and mapping of the human and mouse neuronal β2-nicotinic acetylcholine receptor genes

Novel CHRNA3 variants identified in a patient with bladder dysfunction, dysautonomia, and gastrointestinal dysmotility

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