HGNC Approved Gene Symbol: CHAT
SNOMEDCT: 230670003;
Cytogenetic location: 10q11.23 Genomic coordinates (GRCh38) : 10:49,609,095-49,667,942 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q11.23 | Myasthenic syndrome, congenital, 6, presynaptic | 254210 | Autosomal recessive | 3 |
Choline acetyltransferase (CHAT; EC 2.3.1.6) is the biosynthetic enzyme for the neurotransmitter acetylcholine in the central and peripheral nervous systems (summary by Toussaint et al., 1992).
Toussaint et al. (1992) isolated and partially sequenced a human CHAT genomic clone. The fragment they studied contained the first 4 exons with an AUG initiator codon and potential control regions including TATA, CAAT, GC boxes, and several transcription control sequences. By analyzing cDNAs from mouse spinal cord, Misawa et al. (1992) demonstrated 7 polymorphic forms of CHAT resulting from the alternative splicing of three 5-prime exons named R, N, and M to exon 1, which contains the ATG initiation codon. Chireux et al. (1995) identified 2 alternative first exons in human choline acetyltransferase. They found regions homologous to rodent exons R and M but found that rodent exon N was not conserved in the human gene. Barrard et al. (1987) isolated a cDNA clone encoding the complete sequence of porcine CHAT.
By use of the porcine Chat clone in the study of DNA from a panel of human-rodent somatic cell hybrids, Cohen-Haguenauer et al. (1990) demonstrated that the CHAT gene is located on human chromosome 10. Strauss et al. (1991) regionalized the assignment to 10q11-q22.2 by in situ hybridization. Viegas-Pequignot et al. (1991) used a human choline acetyltransferase genomic sequence and in situ hybridization studies to sublocalize the gene to 10q11.2.
Cholinergic neurotransmission requires uptake of extracellular choline, biosynthesis of acetylcholine from choline and acetyl-coenzyme A, accumulation of acetylcholine into synaptic vesicles driven by proton antiport, and quantal release of acetylcholine from synaptic vesicles triggered by electrical depolarization of the cholinergic neuron (summary by Erickson et al., 1994). Erickson et al. (1994) identified a rat protein (VACHT; 600336) homologous to C. elegans UNC-17, based on reconstitution of acetylcholine transport in a fibroblast cell line transfected with a clone from a rat pheochromocytoma cDNA library encoding this protein. The distribution of VACHT mRNA coincided with that reported for CHAT in the peripheral and central cholinergic nervous system. Furthermore, Erickson et al. (1994) found that the VACHT gene mapped to the same chromosomal location, 10q11.2. The entire sequence of the human VACHT cDNA was contained uninterrupted within the first intron of the CHAT gene locus. Transcription of VACHT and CHAT mRNA from the same or contiguous promoters within the single regulatory locus provided a previously undescribed genetic mechanism for coordinate regulation of 2 proteins whose expression is required to establish a mammalian neuronal phenotype.
Presynaptic Congenital Myasthenic Syndrome 6
Mutations in genes encoding choline acetyltransferase affecting motility have been described in C. elegans and Drosophila. Ohno et al. (2001) described the first mutations in human CHAT. The mutations were identified in presynaptic congenital myasthenic syndrome-6 (CMS6; 254210) associated with frequently fatal episodes of apnea. Studies of the neuromuscular junction in this disorder showed a stimulation-dependent decrease of the amplitude of the miniature endplate potential and no deficiency of the acetylcholine receptor. These findings pointed to a defect in acetylcholine resynthesis or vesicular filling and to CHAT as one of the candidate genes. Direct sequencing of CHAT demonstrated 10 recessive mutations in 5 patients with CMS6. One mutation was a frameshifting null mutation: 523insCC (118490.0001). Three missense mutations, I305T (118490.0009), R420C (118490.0010), and E441K (118490.0003), markedly reduced CHAT expression in COS cells. Kinetic studies of 9 bacterially expressed CHAT mutants demonstrated that 1 mutant, E441K, lacked catalytic activity, and 8 mutants had significantly impaired catalytic efficiencies.
The 5 patients in whom Ohno et al. (2001) demonstrated mutations of the CHAT gene ranged from age 4 to age 40 at the time of report. Four were male and 1 female. All had myasthenic symptoms since birth or early infancy, negative tests for anti-AChR antibodies, and abrupt episodic crises with increased weakness, bulbar paralysis, and apnea precipitated by undue exertion, fever, or excitement. One of the patients had 3 affected sibs and another had 2; 3 of the 5 affected sibs died during febrile episodes, and 1 died suddenly without apparent cause.
Associations Pending Confirmation
Harold et al. (2003) stated that there was substantial evidence for a susceptibility gene for late-onset Alzheimer disease (AD) on chromosome 10. One of the characteristic features of AD is the degeneration and dysfunction of the cholinergic system. The CHAT gene maps to the linked region of chromosome 10 and was therefore considered both a positional and a functional candidate gene for late-onset AD. Harold et al. (2003) screened for variants of the CHAT gene in patients with AD and found that none of the 14 variants they identified showed association with AD.
Old Danish pointing dogs are susceptible to a recessively inherited muscle disease similar to myasthenic diseases in humans. Proschowsky et al. (2007) sequenced the canine Chat gene and found that all affected dogs in 3 litters were homozygous for a G-to-A missense mutation in exon 6 that resulted in substitution of an evolutionarily conserved valine for a methionine. The parents of the affected dogs were heterozygous carriers, and both homozygotes for the normal allele and heterozygous carriers were identified among the healthy littermates.
Mutations in the superoxide dismutase-1 (SOD1; 147450) gene cause familial amyotrophic lateral sclerosis (ALS1; 105400), likely due to the toxic properties of misfolded mutant SOD1 protein. Tateno et al. (2009) demonstrated that, starting from the pre-onset stage of ALS, misfolded SOD1 species associated specifically with Kifap3 (601836) in the ventral white matter of SOD1G93A-transgenic mouse spinal cord. KIFAP3 is responsible for binding to cargoes including choline acetyltransferase as a component of the kinesin-2 motor complex. Motor axons in SOD1G93A-Tg mice also showed a reduction in ChAT transport from the pre-onset stage. Using a purified hybrid mouse neuroblastoma/rat glioma cell line NG108-15 transfected with SOD1 mutations, the authors showed that microtubule-dependent release of acetylcholine was significantly impaired by misfolded SOD1 species and that impairment was normalized by KIFAP3 overexpression. KIFAP3 was incorporated into SOD1 aggregates in spinal motor neurons from human ALS patients as well. Tateno et al. (2009) suggested that KIFAP3 sequestration by misfolded SOD1 species and the resultant inhibition of ChAT transport play a role in the pathophysiology of ALS.
In a 26-year-old patient with congenital myasthenic syndrome-6 (CMS6; 254210) associated with episodic apnea, Ohno et al. (2001) found compound heterozygosity for 2 mutations in the CHAT gene: a frameshift mutation, 523insCC, in exon 6, and a missense mutation, pro211-to-ala (P211A; 118490.0002), due to a 931C-G transversion in exon 7.
For discussion of the pro211-to-ala (P211A) mutation in the CHAT gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-6 (CMS6; 254210) by Ohno et al. (2001), see 118490.0001.
Ohno et al. (2001) found compound heterozygosity for 2 missense mutations in the CHAT gene in a 40-year-old patient with congenital myasthenic syndrome-6 (CMS6; 254210) associated with episodic apnea. The 2 mutations were a 1371G-A transition in exon 12 resulting in a glu441-to-lys (E441K) substitution, and a 1516G-T transversion in exon 14 resulting in a val506-to-leu (V506L; 118490.0004) substitution.
For discussion of the val506-to-leu (V506L) mutation in the CHAT gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-6 (CMS6; 254210) by Ohno et al. (2001), see 118490.0003.
In a 5-year-old patient with congenital myasthenic syndrome-6 (CMS6; 254210) with episodic apnea, Ohno et al. (2001) found compound heterozygosity for 2 missense mutations in the CHAT gene: a 1444A-G transition in exon 13 resulting in an arg482-to-gly (R482G) substitution, and a 1679G-A transition in exon 15 resulting in an arg560-to-his (R560H; 118490.0006) substitution.
For discussion of the arg560-to-his (R560H) mutation in the CHAT gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-6 (CMS6; 254210) by Ohno et al. (2001), see 118490.0005.
In a 6-year-old child with congenital myasthenic syndrome-6 (CMS6; 254210) with episodic apnea, Ohno et al. (2001) found compound heterozygosity for 2 missense mutations in the CHAT gene: a 629T-C transition in exon 7 resulting in a leu210-to-pro (L210P) substitution, and a 1493C-T transition in exon 13 resulting in a ser498-to-leu (S498L; 118490.0008) substitution.
For discussion of the ser498-to-leu (S498L) mutation in the CHAT gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-6 (CMS6; 254210) by Ohno et al. (2001), see 118490.0007.
In a 4-year-old child with congenital myasthenic syndrome-6 (CMS6; 254210) with episodic apnea, Ohno et al. (2001) found compound heterozygosity for 2 missense mutations in the CHAT gene: a 914T-C transition in exon 9 resulting in an ile305-to-thr (I305T) substitution, and a 1258C-T transition in exon 11 resulting in an arg420-to-cys (R420C; 118490.0010) substitution.
For discussion of the arg420-to-cys (R420C) mutation in the CHAT gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-6 (CMS6; 254210) by Ohno et al. (2001), see 118490.0009.
In a consanguineous Turkish family in which 2 sibs had congenital myasthenic syndrome-6 (CMS6; 254210) with episodic apnea, Kraner et al. (2003) identified a homozygous 1187T-C transition in exon 7 of the CHAT gene, resulting in an ile336-to-thr (I336T) substitution. The unaffected parents were heterozygous for the mutation, which was absent in 164 control chromosomes.
Barrard, B. A., Lottspeich, F., Braun, A., Barde, Y. A., Mallet, J. cDNA cloning and complete sequence of porcine choline acetyltransferase: in vitro translation of the corresponding RNA yields an active protein. Proc. Nat. Acad. Sci. 84: 9280-9284, 1987. [PubMed: 3480542] [Full Text: https://doi.org/10.1073/pnas.84.24.9280]
Chireux, M. A., Le Van Thai, A., Weber, M. J. Human choline acetyltransferase gene: localization of alternative first exons. J. Neurosci. Res. 40: 427-438, 1995. [PubMed: 7616604] [Full Text: https://doi.org/10.1002/jnr.490400402]
Cohen-Haguenauer, O., Brice, A., Berrard, S., Van Cong, N., Mallet, J., Frezal, J. Localization of the choline acetyltransferase (CHAT) gene to human chromosome 10. Genomics 6: 374-378, 1990. [PubMed: 2307477] [Full Text: https://doi.org/10.1016/0888-7543(90)90579-j]
Erickson, J. D., Varoqui, H., Schafer, M. K.-H., Modi, W., Diebler, M.-F., Weihe, E., Rand, J., Eiden, L. E., Bonner, T. I., Usdin, T. B. Functional identification of a vesicular acetylcholine transporter and its expression from a 'cholinergic' gene locus. J. Biol. Chem. 269: 21929-21932, 1994. [PubMed: 8071310]
Harold, D., Peirce, T., Moskvina, V., Myers, A., Jones, S., Hollingworth, P., Moore, P., Lovestone, S., Powell, J., Foy, C., Archer, N., Walter, S., and 11 others. Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease. Hum. Genet. 113: 258-267, 2003. [PubMed: 12759818] [Full Text: https://doi.org/10.1007/s00439-003-0960-2]
Kraner, S, Laufenberg, I., Strassburg, H. M., Sieb, J. P., Steinlein, O. K. Congenital myasthenic syndrome with episodic apnea in patients homozygous for a CHAT missense mutation. Arch. Neurol. 60: 761-763, 2003. [PubMed: 12756141] [Full Text: https://doi.org/10.1001/archneur.60.5.761]
Misawa, H., Ishii, K., Deguchi, T. Gene expression of mouse choline acetyltransferase: alternative splicing and identification of a highly active promoter region. J. Biol. Chem. 267: 20392-20399, 1992. [PubMed: 1400357]
Ohno, K., Tsujino, A., Brengman, J. M., Harper, C. M., Bajzer, Z., Udd, B., Beyring, R., Robb, S., Kirkham, F. J., Engel, A. G. Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proc. Nat. Acad. Sci. 98: 2017-2022, 2001. [PubMed: 11172068] [Full Text: https://doi.org/10.1073/pnas.98.4.2017]
Proschowsky, H. F., Flagstad, A., Cirera, S., Joergensen, C. B., Fredholm, M. Identification of a mutation in the CHAT gene of Old Danish Pointing Dogs affected with congenital myasthenic syndrome. J. Hered. 98: 539-543, 2007. [PubMed: 17586598] [Full Text: https://doi.org/10.1093/jhered/esm026]
Strauss, W. L., Kemper, R. R., Jayakar, P., Kong, C. F., Hersh, L. B., Hilt, D. C., Rabin, M. Human choline acetyltransferase gene maps to region 10q11-q22.2 by in situ hybridization. Genomics 9: 396-398, 1991. [PubMed: 1840566] [Full Text: https://doi.org/10.1016/0888-7543(91)90273-h]
Tateno, M., Kato, S., Sakurai, T., Nukina, N., Takahashi, R., Araki, T. Mutant SOD1 impairs axonal transport of choline acetyltransferase and acetylcholine release by sequestering KAP3. Hum. Molec. Genet. 18: 942-955, 2009. [PubMed: 19088126] [Full Text: https://doi.org/10.1093/hmg/ddn422]
Toussaint, J. L., Geoffroy, V., Schmitt, M., Werner, A., Garnier, J. M., Simoni, P., Kempf, J. Human choline acetyltransferase (CHAT): partial gene sequence and potential control regions. Genomics 12: 412-416, 1992. [PubMed: 1339386] [Full Text: https://doi.org/10.1016/0888-7543(92)90395-9]
Viegas-Pequignot, E., Berrard, S., Brice, A., Apiou, F., Mallet, J. Localization of a 900-bp-long fragment of the human choline acetyltransferase gene to 10q11.2 by nonradioactive in situ hybridization. Genomics 9: 210-212, 1991. [PubMed: 2004764] [Full Text: https://doi.org/10.1016/0888-7543(91)90242-7]