Alternative titles; symbols
HGNC Approved Gene Symbol: COLQ
Cytogenetic location: 3p25.1 Genomic coordinates (GRCh38): 3:15,450,133-15,521,706 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p25.1 | Myasthenic syndrome, congenital, 5 | 603034 | Autosomal recessive | 3 |
The COLQ gene encodes a collagen-like strand that associates into a triple helix to form a tail that anchors catalytic subunits of acetylcholinesterase (ACHE; 100740) to the basal lamina.
Asymmetric AChE is the major form of AChE at the endplate of the neuromuscular junction in higher vertebrates. Asymmetric AChE is composed of the T isoform of ACHE, ACHE(T), linked to a triple helical COLQ tail. AChE rapidly hydrolyzes acetylcholine released at cholinergic synapses in the nervous system, thus limiting the number of collisions between ACh and the ACh receptor (AChR), and the duration of the synaptic response (Ohno et al., 1998).
Krejci et al. (1991) cloned ColQ from Torpedo. Krejci et al. (1997) cloned the rat and mouse ColQ genes, and found that the ColQ subunits form homotrimers and attach to AChE. Northern blot analysis detected ColQ expression in cholinergic tissues, brain, muscle, and heart, as well as in noncholinergic tissues such as lung and testes.
Ohno et al. (1998) used mouse ColQ primers to isolate human COLQ cDNA from a human adult skeletal muscle cDNA library. The cDNA encodes a deduced 455-amino acid protein with 89% homology to the rodent ColQ peptide. Conserved domains include a secretion signal peptide, a proline-rich attachment domain (PRAD) that interacts with AChE(T), 2 cysteines that form disulfide bonds with AChE(T), a collagen domain, conserved cysteines that stabilize the triple helical domain, and proteoglycan binding domains that anchor the triple helical domain to the basal lamina. Several alternative transcripts were identified.
Ohno et al. (1998) determined that the COLQ gene spans approximately 50 kb and comprises 17 constitutive exons and 2 alternatively transcribed exons.
By fluorescence in situ hybridization, Ohno et al. (1998) mapped the COLQ gene to chromosome 3p25. By radiation hybrid analysis, Donger et al. (1998) mapped the COLQ gene to chromosome 3p24.2.
In patients with congenital myasthenic syndrome-5 (CMS5; 603034) due to endplate AChE deficiency (EAD), Ohno et al. (1998) identified 6 recessive mutations in the COLQ gene (603033.0001-603033.0006). Coexpression of each of the 6 ColQ mutants with wildtype AChE(T) in SV40-transformed monkey kidney fibroblast (COS) cells showed that a mutation proximal to the ColQ attachment domain for AChE(T) prevented association of ColQ with AChE(T); mutations distal to the attachment domain generated a mutant species of acetylcholinesterase composed of 1 AChE(T) tetramer and a truncated ColQ strand. The authors concluded that the mutations prevented the insertion of the gene product into the basal lamina.
In 6 sibs with a mild form of endplate AChE deficiency, Donger et al. (1998) identified a homozygous mutation in the COLQ gene (603033.0007).
Shapira et al. (2002) reported 3 novel mutations in the COLQ gene in 8 patients with variable features of EAD: 1 patient was a compound heterozygote; the other 7 patients, 6 Palestinian Arabs and 1 Iraqi Jew, were all homozygous for a gly240-to-ter mutation (G240X; 603033.0010), suggesting a founder mutation. Expression studies of the 3 mutations in COS-7 cells showed that each prevented formation of insertion competent asymmetric AChE.
Feng et al. (1999) generated ColQ -/- mice to study the roles played by ColQ and AChE in synapses and elsewhere. Such mice failed to thrive and most died before reaching maturity. They completely lacked asymmetric AChE in skeletal and cardiac muscles, specifically at the neuromuscular junction (NMJ) and in the brain. Nonetheless, neuromuscular function was present. A compensatory mechanism appeared to be a partial ensheathment of nerve terminals by Schwann cells. Such mice also lacked the asymmetric forms of Bche (177400). Surprisingly, globular AChE tetramers were absent as well, suggesting a role for the ColQ gene in assembly or stabilization of AChE forms that do not contain a collagenous subunit.
In a patient with congenital myasthenic syndrome-5 (CMS5; 603034), Ohno et al. (1998) found compound heterozygous mutations in the COLQ gene: a deletion of 215 basepairs following nucleotide 107 of the COLQ gene and an E214X substitution (603033.0002). The deletion was caused by skipping of exons 2 and 3, causing a frameshift after codon 35. The mutation abolished the proline-rich attachment domain (PRAD) and predicted 25 missense codons followed by a stop codon. The deletion mutation was inherited from the mother and the truncating mutation from the father.
For discussion of the glu214-to-ter (E214X) mutation in the COLQ gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-5 (CMS5; 603034) by Ohno et al. (1998), see 603033.0001.
In a patient with CMS5, Ohno et al. (1998) identified homozygosity for the E214X mutation.
In a patient with congenital myasthenic syndrome-5 (CMS5; 603034), originally reported by Engel et al. (1977), Ohno et al. (1998) identified a homozygous ser169-to-ter (S169X) mutation, which resulted in loss of the distal two-thirds of the collagen domain.
In a patient with congenital myasthenic syndrome-5 (CMS5; 603034), Ohno et al. (1998) identified compound heterozygosity for 2 mutations in the COLQ gene: an arg282-to-ter (R282X) mutation and a 1-bp deletion (1082delC; 603033.0005). The R282X mutation truncated COLQ 10 codons upstream to the C-terminal end of the collagen domain. The 1-bp deletion caused a frameshift after codon 360, predicting 64 missense codons followed by a stop codon; 1082delC spared the entire collagen domain but abolished the C-terminal domain of COLQ.
For discussion of the 1082delC mutation in the COLQ gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-5 (CMS5; 603034) by Ohno et al. (1998), see 603033.0004.
In a patient with CMS5, Ohno et al. (1998) identified homozygosity for the c.1082delC mutation. The asymptomatic parents were heterozygous for the mutation.
In a patient with congenital myasthenic syndrome-5 (CMS5; 603034), Ohno et al. (1998) identified a homozygous 1-bp insertion (788insC) in the COLQ gene that caused a frameshift after codon 262, predicting 36 missense codons followed by a stop codon. The c.788insC mutation spared 85% of the collagen domain. The asymptomatic parents were heterozygous for the mutation.
In 6 affected sibs from a consanguineous Spanish family with congenital myasthenic syndrome-5 (CMS5; 603034), Donger et al. (1998) identified a homozygous tyr431-to-ser (Y431S) substitution in the conserved C-terminal domain of COLQ. The mutation was predicted to disturb the attachment of collagen-tailed acetylcholinesterase to the neuromuscular junction (NMJ). Donger et al. (1998) referred to the disorder in these patients as CMS Ic (for congenital myasthenic syndrome type Ic). The authors noted that most previously described CMS Ic patients had a marked decrease in total muscle acetylcholinesterase with essentially no collagen-tailed forms. These forms were present in affected members of the Spanish family, but the defect interfered with attachment to the NMJ.
Ohno et al. (1999) described a patient with congenital myasthenic syndrome-5 (CMS5; 603034) caused by compound heterozygosity for an arg315-to-ter (R315X) mutation and a splice donor site mutation at position +3 of intron 16 of COLQ (603033.0009).
Ohno et al. (1999) described a patient with congenital myasthenic syndrome-5 (CMS5; 603034) caused by compound heterozygosity for 2 mutations in the COLQ gene: an arg315-to-ter (R315X; 603033.0008) mutation and a splice donor site mutation at position +3 of intron 16 (IVS16+3A-G). Using a minigene harboring the IVS16+3A-G mutation for functional expression studies, Ohno et al. (1999) found that the splice site mutation resulted in skipping of exon 16. The mutant splice donor site of intron 16 harbors 5 discordant nucleotides (at -3, -2, +3, +4, and +6) that do not basepair with U1 small nuclear (sn) RNA (RNU1; 180680), the RNA responsible for splice donor site recognition. Versions of the minigene harboring, at either +4 or +6, nucleotides complementary to U1 snRNA restored normal splicing. Analysis of 1,801 native splice donor sites revealed that the presence of a G nucleotide at +3 is associated with preferential usage, at positions +4 to +6, of nucleotides concordant to U1 snRNA. Analysis of 11 disease-associated IVS+3A-G mutations indicated that, on average, 2 of 3 nucleotides at positions +4 to +6 failed to basepair, and that the nucleotide at +4 never basepaired, with U1 snRNA. Ohno et al. (1999) concluded that, with G at +3, normal splicing generally depends on the concordance that residues at +4 to +6 have with U1 snRNA, but other cis-acting elements may also be important in assuring the fidelity of splicing.
In 6 Palestinian Arabs and 1 Iraqi Jew with variable features of congenital myasthenic syndrome-5 (CMS5; 603034), Shapira et al. (2002) identified a homozygous 718G-T transversion in a splice acceptor consensus sequence of exon 12 of the COLQ gene, resulting in a gly240-to-ter (G240X) mutation and causing premature termination of the protein. The mutation prevented proper formation of asymmetric AChE in COS-7 cells. The patients demonstrated phenotypic variability, including differences in age of onset and disease progression, respiratory and feeding difficulties, severity of weakness, and ophthalmoplegia.
Donger, C., Krejci, E., Serradell, A. P., Eymard, B., Bon, S., Nicole, S., Chateau, D., Gary, F., Fardeau, M., Massoulie, J., Guicheney, P. Mutation in the human acetylcholinesterase-associated collagen gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency (type Ic). Am. J. Hum. Genet. 63: 967-975, 1998. [PubMed: 9758617] [Full Text: https://doi.org/10.1086/302059]
Engel, A. G., Lambert, E. H., Gomez, M. R. A new myasthenic syndrome with end-plate acetylcholinesterase deficiency, small nerve terminals, and reduced acetylcholine release. Ann. Neurol. 1: 315-330, 1977. [PubMed: 214017] [Full Text: https://doi.org/10.1002/ana.410010403]
Feng, G., Krejci, E., Molgo, J., Cunningham, J. M., Massoulie, J., Sanes, J. R. Genetic analysis of collagen Q: roles in acetylcholinesterase and butyrylcholinesterase assembly and in synaptic structure and function. J. Cell Biol. 144: 1349-1360, 1999. [PubMed: 10087275] [Full Text: https://doi.org/10.1083/jcb.144.6.1349]
Krejci, E., Coussen, F., Duval, N., Chatel, J.-M., Legay, C., Puype, M., Vandekerckhove, J., Cartaud, J., Bon, S., Massoulie, J. Primary structure of a collagenic tail peptide of torpedo acetylcholinesterase: co-expression with catalytic subunit induces the production of collagen-tailed forms in transfected cells. EMBO J. 10: 1285-1293, 1991. [PubMed: 1840520] [Full Text: https://doi.org/10.1002/j.1460-2075.1991.tb08070.x]
Krejci, E., Thomine, S., Boschetti, N., Legay, C., Sketelj, J., Massoulie, J. The mammalian gene of acetylcholinesterase-associated collagen. J. Biol. Chem. 272: 22840-22847, 1997. [PubMed: 9278446] [Full Text: https://doi.org/10.1074/jbc.272.36.22840]
Ohno, K., Brengman, J., Tsujino, A., Engel, A. G. Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme. Proc. Nat. Acad. Sci. 95: 9654-9659, 1998. [PubMed: 9689136] [Full Text: https://doi.org/10.1073/pnas.95.16.9654]
Ohno, K., Brengman, J. M., Felice, K. J., Cornblath, D. R., Engel, A. G. Congenital end-plate acetylcholinesterase deficiency caused by a nonsense mutation and an A-to-G splice-donor-site mutation at position +3 of the collagenlike-tail-subunit gene (COLQ): how does G at position +3 result in aberrant splicing? Am. J. Hum. Genet. 65: 635-644, 1999. [PubMed: 10441569] [Full Text: https://doi.org/10.1086/302551]
Shapira, Y. A., Sadeh, M. E., Bergtraum, M. P., Tsujino, A., Ohno, K., Shen, X.-M., Brengman, J., Edwardson, S., Matoth, I., Engel, A. G. Three novel COLQ mutations and variation of phenotypic expressivity due to G240X. Neurology 58: 603-609, 2002. [PubMed: 11865139] [Full Text: https://doi.org/10.1212/wnl.58.4.603]