Alternative titles; symbols
HGNC Approved Gene Symbol: CHRM3
SNOMEDCT: 5187006; ICD10CM: Q79.4; ICD9CM: 756.71;
Cytogenetic location: 1q43 Genomic coordinates (GRCh38): 1:239,386,568-239,915,450 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q43 | Prune belly syndrome | 100100 | Autosomal recessive | 3 |
Muscarinic acetylcholine receptors (see 118510) are G protein-linked 7-transmembrane receptors that are present throughout the body in smooth muscle, cardiac muscle, exocrine glands, and neurons of the central and peripheral nervous systems. Some muscarinic receptors, such as CHRM3, interact with pertussis toxin-insensitive Gq proteins (see 600998) and activate phospholipase C (see 607120), whereas others preferentially interact with pertussis toxin-sensitive Gi proteins (see 139310) and inhibit adenylyl cyclase. CHRM3 is the predominant muscarinic receptor mediating acetylcholine-induced airway smooth muscle contraction, and it plays a role in the regulation of intracellular calcium in bronchial epithelium (summary by Forsythe et al., 2002). In addition, CHRM3 mediates autonomic neurotransmission in the ocular iris pupillary sphincter and the detrusor muscle in humans (Pomper et al., 2011).
By 5-prime RACE of bronchial epithelial cell RNA, PCR of a 5-prime RACE cDNA library generated from trachea RNA, and EST database analysis, Forsythe et al. (2002) identified human CHRM3 splice variants that exclude the noncoding exons 2, 4, 6, and/or 7.
By searching databases and published reports, as well as by RT-PCR, Huh et al. (2009) identified 5 CHRM3 splice variants that they designated T1, T2, T3, T3-1, and T4. T2 and T4 use a conserved upstream promoter, T3 and T3-1 use an internal promoter related to the THE1C transposable element, and T1 uses an internal promoter related to the L1HS transposable element. T2 encodes a deduced 590-amino acid protein. RT-PCR detected expression of T2 and T4 in several human tissues and specific brain regions, predominantly hippocampus, corpus callosum, and various cortical regions. T1 was detected predominantly in placenta, and T3 and T3-1 were detected predominantly in testis.
Forsythe et al. (2002) determined that the CHRM3 gene contains 8 exons and spans at least 285 kb. Exon 1 contains a cluster of transcriptional start sites, exons 2, 4, 6, and 7 are subject to alternative splicing, and exon 8 contains the entire coding region. The 5-prime flanking region is GC rich and contains several potential AP2 (TFAP2A; 107580)-binding sites. It has no TATA or CAAT box. Reporter assays confirmed the presence of functional AP2 sites.
Huh et al. (2009) determined that the CHRM3 gene contains up to 13 alternatively spliced exons. Only the last exon contains the coding region. CHRM3 has an evolutionarily conserved upstream promoter region and downstream promoters related to THE1C and L1HS transposable elements.
Bonner (1990) indicated that the CHRM3 gene maps to chromosome 1q41-q44 by in situ hybridization.
Stumpf (2020) mapped the CHRM3 gene to chromosome 1q43 based on an alignment of the CHRM3 sequence (GenBank BC121026) with the genomic sequence (GRCh38).
The M3 cholinergic receptor mediates autonomic neurotransmission in the ocular iris pupillary sphincter and the detrusor muscle in humans. Pomper et al. (2011) reported a male patient who presented at age 37 years with an almost complete loss of ability to empty his bladder, resulting in recurrent bladder infections, formation of urinary stones, and unilateral kidney dysfunction. He had a lean habitus since childhood. Urologic testing revealed detrusor acontractility. He was found to have mydriasis not responding to light, near vision, or pilocarpine, and decreased sweating. The findings were consistent with a defect of the M3 receptor in the detrusor and pupillary sphincter muscles, as observed in Chrm3-null mice (see ANIMAL MODEL). Although Western blot analysis of patient lymphocytes and skin and bladder lysates showed reduced CHRM3 protein expression, mRNA levels were normal. Sequence analysis and quantitative PCR analysis showed no mutations or copy number variation of the CHRM3 gene. Laboratory studies showed that the patient had a positive nonspecific antinuclear antibody titer.
Crystal Structure
Kruse et al. (2012) described the structure of the Gq (600998)/G11 (139313)-coupled M3 muscarinic acetylcholine receptor (M3 receptor from rat) bound to the bronchodilator drug tiotropium and identified the binding mode for this clinically important drug. The structure, together with that of the Gi (139310)/Go (139311)-coupled M2 receptor (CHRM2; 118493), offers possibilities for the design of muscarinic acetylcholine receptor subtype-selective ligands. Importantly, the M3 receptor structure allows a structural comparison between 2 members of a mammalian G protein-coupled receptor (GPCR) subfamily displaying different G protein-coupling selectivities. Furthermore, molecular dynamics simulations suggested that tiotropium binds transiently to an allosteric site en route to the binding pocket of both receptors. These simulations offered a structural view of an allosteric binding mode for an orthosteric GPCR ligand and provided additional opportunities for the design of ligands with different affinities or binding kinetics for different muscarinic acetylcholine receptor subtypes.
In a consanguineous Turkish family with prune belly syndrome (PBS; 100100), Weber et al. (2011) identified a homozygous frameshift mutation in the CHRM3 gene on chromosome 1q43 (118494.0001) that segregated with disease. Affected individuals also had bilaterally impaired pupillary constriction and dry mouths. Weber et al. (2011) noted that the phenotype in this family was strikingly similar to that of the patient described by Pomper et al. (2011).
In 2 affected sisters from a consanguineous Malaysian family with hypocontractile bladder and impaired pupillary constriction to light, Beaman et al. (2019) identified homozygosity for a missense mutation in the CHRM3 gene (G118R; 118494.0002). The mutation segregated fully with disease in the family and was not found in the gnomAD database.
Matsui et al. (2000) found that homozygous Chrm3-null mice showed transient postweaning growth retardation compared to wildtype mice, and normal reproduction. Homozygous mutant mice had dilated ocular pupils, and neither pupils nor salivary glands responded well to administration of the muscarinic agonist pilocarpine compared to wildtype. Male mutant mice, but not female mutant mice, had severely distended urinary bladders resulting from impaired contractility of the detrusor smooth muscle, as measured in vitro. There was also impaired contractility of the ileal smooth muscle in vitro, but no clinical gastrointestinal complications. Matsui et al. (2000) concluded that Chrm3 is important in parasympathetic-mediated salivation and constriction of the pupillary muscle in both sexes, and is responsible for about 95% of detrusor muscle contraction in male mice.
Members of the muscarinic acetylcholine receptor family have central roles in the regulation of many fundamental physiologic functions. Identifying the specific subtype(s) that mediate the diverse muscarinic actions of acetylcholine is of considerable therapeutic interest, but has proved difficult primarily because of a lack of subtype-selective ligands. Yamada et al. (2001) showed that mice deficient in the M3 muscarinic receptor display a significant decrease in food intake, reduced body weight and peripheral fat deposits, and very low levels of serum leptin and insulin. Paradoxically, hypothalamic mRNA levels of melanin-concentrating hormone (MCH; 176795), which are normally upregulated in fasted animals leading to an increase in food intake, are significantly reduced in M3r -/- mice. Intracerebroventricular injection studies showed than an agouti-related peptide (602311) analog lacked orexigenic (appetite-stimulating) activity in M3r -/- mice. However, M3r -/- mice remained responsive to the orexigenic effects of MCH. Yamada et al. (2001) concluded that there may be a cholinergic pathway that involves M3-receptor-mediated facilitation of food intake at a site downstream of the hypothalamic leptin (164160)/melanocortin (176830) system and upstream of the MCH system.
Using a CRISPR/Cas9 system, Niwa et al. (2018) created Chrm1 (118510) and Chrm3 knockout mice and found that these metabotropic cholinergic receptors have a crucial and redundant role in sleep. Chrm1 knockout mice had reduced duration of both rapid eye movement (REM) sleep and non-REM (NREM) sleep, demonstrating that Chrm1 has a role in regulating the duration of REM sleep but also contributes to the duration of NREM sleep. In contrast, Chrm3 knockout mice showed reduction of the duration of NREM sleep only. While the duration of REM sleep in Chrm3 knockout mice did not change, REM sleep became fragmented, demonstrating that Chrm3 has a role in regulating the duration of NREM sleep but also contributes to the consolidation of REM sleep. Furthermore, REM sleep was almost completely abolished in Chrm1 and Chrm3 double-knockout mice. Niwa et al. (2018) concluded that their findings provided evidence that cholinergic signaling is indeed essential for generating REM sleep.
In affected brothers of a consanguineous Turkish family with prune belly syndrome (PBS; 100100), previously studied by Weber et al. (2005), Weber et al. (2011) identified homozygosity for a 12-bp deletion/1-bp insertion (1173_1184delinsT, NM_000740.2) in the CHRM3 gene, resulting in a frameshift and premature termination (Pro392AlafsTer43). The unaffected first-cousin parents and an unaffected sister were heterozygous for the mutation, which was not found in 374 Turkish control chromosomes. Two of 6 affected brothers had the full triad of prune belly syndrome, whereas the remaining 4 had malformed bladders only; 3 of the sibs had chronic renal disease. Affected individuals also had bilaterally impaired pupillary constriction to light and dry mouths.
In 2 sisters from a consanguineous Malaysian family with hypocontractile bladder and impaired pupillary constriction to light (PBS; 100100), Beaman et al. (2019) performed targeted sequencing of 13 genes associated with urinary bladder voiding and identified homozygosity for a c.352G-A transition (c.352G-A, NM_000740.3) in the CHRM3 gene, resulting in a gly118-to-arg (G118R) substitution at a highly conserved residue within the second transmembrane domain. Their unaffected parents and 3 unaffected sibs were heterozygous for the mutation, which was not found in the gnomAD database. Functional studies of the mutation were not performed.
Beaman, G. M., Galata, G., Teik, K. W., Urquhart, J. E., Aishah, A., O'Sullivan, J., Bhaskar, S. S., Wood, K. A., Thomas, H. B., O'Keefe, R. T., Woolf, A. S., Stuart, H. M., Newman, W. G. A homozygous missense variant in CHRM3 associated with familial urinary bladder disease. Clin. Genet. 96: 515-520, 2019. [PubMed: 31441039] [Full Text: https://doi.org/10.1111/cge.13631]
Bonner, T. I. Personal Communication. Bethesda, Md. 9/21/1990.
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Huh, J.-W., Kim, Y.-H., Lee, S.-R., Kim, H., Kim, D.-S., Kim, H.-S., Kang, H.-S., Chang, K.-T. Gain of new exons and promoters by lineage-specific transposable elements-integration and conservation event on CHRM3 gene. Molec. Cells 28: 111-117, 2009. [PubMed: 19669628] [Full Text: https://doi.org/10.1007/s10059-009-0106-z]
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Matsui, M., Motomura, D., Karasawa, H., Fujikawa, T., Jiang, J., Komiya, Y., Takahashi, S., Taketo, M. M. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc. Nat. Acad. Sci. 97: 9579-9584, 2000. [PubMed: 10944224] [Full Text: https://doi.org/10.1073/pnas.97.17.9579]
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Pomper, J. K., Wilhelm, H., Tayebati, S. K., Asmus, F., Schule, R., Sievert, K.-D., Haensch, C.-A., Melms, A., Haarmeier, T. A novel clinical syndrome revealing a deficiency of the muscarinic M3 receptor. Neurology 76: 451-455, 2011. [PubMed: 21282591] [Full Text: https://doi.org/10.1212/WNL.0b013e31820a0a75]
Stumpf, A. M. Personal Communication. Baltimore, Md. 08/04/2020.
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Yamada, M., Miyakawa, T., Duttaroy, A., Yamanaka, A., Moriguchi, T., Makita, R., Ogawa, M., Chou, C. J., Xia, B., Crawley, J. N., Felder, C. C., Deng, C.-X., Wess, J. Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean. Nature 410: 207-212, 2001. [PubMed: 11242080] [Full Text: https://doi.org/10.1038/35065604]