Mutation in the human acetylcholinesterase-associated collagen gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency (Type Ic) (original) (raw)

Abstract

Congenital myasthenic syndrome (CMS) with end-plate acetylcholinesterase (AChE) deficiency is a rare autosomal recessive disease, recently classified as CMS type Ic (CMS-Ic). It is characterized by onset in childhood, generalized weakness increased by exertion, refractoriness to anticholinesterase drugs, and morphological abnormalities of the neuromuscular junctions (NMJs). The collagen-tailed form of AChE, which is normally concentrated at NMJs, is composed of catalytic tetramers associated with a specific collagen, COLQ. In CMS-Ic patients, these collagen-tailed forms are often absent. We studied a large family comprising 11 siblings, 6 of whom are affected by a mild form of CMS-Ic. The muscles of the patients contained collagen-tailed AChE. We first excluded the ACHE gene (7q22) as potential culprit, by linkage analysis; then we mapped COLQ to chromosome 3p24.2. By analyzing 3p24.2 markers located close to the gene, we found that the six affected patients were homozygous for an interval of 14 cM between D3S1597 and D3S2338. We determined the COLQ coding sequence and found that the patients present a homozygous missense mutation, Y431S, in the conserved C-terminal domain of COLQ. This mutation is thought to disturb the attachment of collagen-tailed AChE to the NMJ, thus constituting the first genetic defect causing CMS-Ic.

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Selected References

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  1. Andres C., Beeri R., Friedman A., Lev-Lehman E., Henis S., Timberg R., Shani M., Soreq H. Acetylcholinesterase-transgenic mice display embryonic modulations in spinal cord choline acetyltransferase and neurexin Ibeta gene expression followed by late-onset neuromotor deterioration. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8173–8178. doi: 10.1073/pnas.94.15.8173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bon S., Cartaud J., Massoulié J. The dependence of acetylcholinesterase aggregation at low ionic strength upon a polyanionic component. Eur J Biochem. 1978 Apr;85(1):1–14. doi: 10.1111/j.1432-1033.1978.tb12207.x. [DOI] [PubMed] [Google Scholar]
  3. Bon S., Coussen F., Massoulié J. Quaternary associations of acetylcholinesterase. II. The polyproline attachment domain of the collagen tail. J Biol Chem. 1997 Jan 31;272(5):3016–3021. doi: 10.1074/jbc.272.5.3016. [DOI] [PubMed] [Google Scholar]
  4. Brandan E., Maldonado M., Garrido J., Inestrosa N. C. Anchorage of collagen-tailed acetylcholinesterase to the extracellular matrix is mediated by heparan sulfate proteoglycans. J Cell Biol. 1985 Sep;101(3):985–992. doi: 10.1083/jcb.101.3.985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bundey S. A genetic study of infantile and juvenile myasthenia gravis. J Neurol Neurosurg Psychiatry. 1972 Feb;35(1):41–51. doi: 10.1136/jnnp.35.1.41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Camp S., Bon S., Li Y., Getman D. K., Engel A. G., Massoulié J., Taylor P. Patients with congenital myasthenia associated with end-plate acetylcholinesterase deficiency show normal sequence, mRNA splicing, and assembly of catalytic subunits. J Clin Invest. 1995 Jan;95(1):333–340. doi: 10.1172/JCI117661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carson S., Bon S., Vigny M., Massoulié J., Fardeau M. Distribution of acetylcholinesterase molecular forms in neural and non-neural sections of human muscle. FEBS Lett. 1979 Jan 15;97(2):348–352. doi: 10.1016/0014-5793(79)80119-2. [DOI] [PubMed] [Google Scholar]
  8. Collins A., Frezal J., Teague J., Morton N. E. A metric map of humans: 23,500 loci in 850 bands. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14771–14775. doi: 10.1073/pnas.93.25.14771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Coussen F., Bonnerot C., Massoulié J. Stable expression of acetylcholinesterase and associated collagenic subunits in transfected RBL cell lines: production of GPI-anchored dimers and collagen-tailed forms. Eur J Cell Biol. 1995 Jul;67(3):254–260. [PubMed] [Google Scholar]
  10. Deprez P. N., Inestrosa N. C. Two heparin-binding domains are present on the collagenic tail of asymmetric acetylcholinesterase. J Biol Chem. 1995 May 12;270(19):11043–11046. doi: 10.1074/jbc.270.19.11043. [DOI] [PubMed] [Google Scholar]
  11. Dib C., Fauré S., Fizames C., Samson D., Drouot N., Vignal A., Millasseau P., Marc S., Hazan J., Seboun E. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996 Mar 14;380(6570):152–154. doi: 10.1038/380152a0. [DOI] [PubMed] [Google Scholar]
  12. ELLMAN G. L., COURTNEY K. D., ANDRES V., Jr, FEATHER-STONE R. M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961 Jul;7:88–95. doi: 10.1016/0006-2952(61)90145-9. [DOI] [PubMed] [Google Scholar]
  13. Ehrlich G., Viegas-Pequignot E., Ginzberg D., Sindel L., Soreq H., Zakut H. Mapping the human acetylcholinesterase gene to chromosome 7q22 by fluorescent in situ hybridization coupled with selective PCR amplification from a somatic hybrid cell panel and chromosome-sorted DNA libraries. Genomics. 1992 Aug;13(4):1192–1197. doi: 10.1016/0888-7543(92)90037-s. [DOI] [PubMed] [Google Scholar]
  14. 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. 1977 Apr;1(4):315–330. doi: 10.1002/ana.410010403. [DOI] [PubMed] [Google Scholar]
  15. Fenichel G. M. Clinical syndromes of myasthenia in infancy and childhood. A review. Arch Neurol. 1978 Feb;35(2):97–103. doi: 10.1001/archneur.1978.00500260035009. [DOI] [PubMed] [Google Scholar]
  16. Getman D. K., Eubanks J. H., Camp S., Evans G. A., Taylor P. The human gene encoding acetylcholinesterase is located on the long arm of chromosome 7. Am J Hum Genet. 1992 Jul;51(1):170–177. [PMC free article] [PubMed] [Google Scholar]
  17. Hall Z. W., Kelly R. B. Enzymatic detachment of endplate acetylcholinesterase from muscle. Nat New Biol. 1971 Jul 14;232(28):62–63. doi: 10.1038/newbio232062a0. [DOI] [PubMed] [Google Scholar]
  18. Helbling-Leclerc A., Zhang X., Topaloglu H., Cruaud C., Tesson F., Weissenbach J., Tomé F. M., Schwartz K., Fardeau M., Tryggvason K. Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. Nat Genet. 1995 Oct;11(2):216–218. doi: 10.1038/ng1095-216. [DOI] [PubMed] [Google Scholar]
  19. Hutchinson D. O., Walls T. J., Nakano S., Camp S., Taylor P., Harper C. M., Groover R. V., Peterson H. A., Jamieson D. G., Engel A. G. Congenital endplate acetylcholinesterase deficiency. Brain. 1993 Jun;116(Pt 3):633–653. doi: 10.1093/brain/116.3.633. [DOI] [PubMed] [Google Scholar]
  20. Jennekens F. G., Hesselmans L. F., Veldman H., Jansen E. N., Spaans F., Molenaar P. C. Deficiency of acetylcholine receptors in a case of end-plate acetylcholinesterase deficiency: a histochemical investigation. Muscle Nerve. 1992 Jan;15(1):63–72. doi: 10.1002/mus.880150112. [DOI] [PubMed] [Google Scholar]
  21. Krejci E., Thomine S., Boschetti N., Legay C., Sketelj J., Massoulié J. The mammalian gene of acetylcholinesterase-associated collagen. J Biol Chem. 1997 Sep 5;272(36):22840–22847. doi: 10.1074/jbc.272.36.22840. [DOI] [PubMed] [Google Scholar]
  22. Massoulié J., Pezzementi L., Bon S., Krejci E., Vallette F. M. Molecular and cellular biology of cholinesterases. Prog Neurobiol. 1993 Jul;41(1):31–91. doi: 10.1016/0301-0082(93)90040-y. [DOI] [PubMed] [Google Scholar]
  23. Middleton L. T. Congenital myasthenic syndromes. 34th ENMC International Workshop, 10-11 June 1995. Neuromuscul Disord. 1996 Mar;6(2):133–136. doi: 10.1016/0960-8966(95)00037-2. [DOI] [PubMed] [Google Scholar]
  24. Rotundo R. L., Rossi S. G., Anglister L. Transplantation of quail collagen-tailed acetylcholinesterase molecules onto the frog neuromuscular synapse. J Cell Biol. 1997 Jan 27;136(2):367–374. doi: 10.1083/jcb.136.2.367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Slonim D., Kruglyak L., Stein L., Lander E. Building human genome maps with radiation hybrids. J Comput Biol. 1997 Winter;4(4):487–504. doi: 10.1089/cmb.1997.4.487. [DOI] [PubMed] [Google Scholar]
  26. Sternfeld M., Ming G., Song H., Sela K., Timberg R., Poo M., Soreq H. Acetylcholinesterase enhances neurite growth and synapse development through alternative contributions of its hydrolytic capacity, core protein, and variable C termini. J Neurosci. 1998 Feb 15;18(4):1240–1249. doi: 10.1523/JNEUROSCI.18-04-01240.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]