Three novel COLQ mutations and variation of phenotypic expressivity due to G240X

Y. A. Shapira, M. E. Sadeh, M. P. Bergtraum, A. Tsujino, K. Ohno, X. M. Shen, J. Brengman, S. Edwardson, I. Matoth, Andrew G Engel

Research output: Contribution to journalArticle

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Abstract

Objective: To determine the molecular basis and consequences of endplate (EP) acetylcholinesterase (AChE) deficiency. Background: The EP species AChE is an asymmetric enzyme consisting of a tail subunit composed of three collagenic strands (ColQ), each attached to a tetramer of catalytic subunits. The tail subunit is essential for insertion of AChE into the synaptic basal lamina. Human EP AChE deficiency is caused by mutations in COLQ. The authors report three novel COLQ mutations in eight kinships. Methods: Immunocytochemistry, electron microscopy, microelectrode recordings, mutation analysis, and expression studies in COS cells were employed. Results: Two mutations (275insC and Q211X) were heterozygous in one patient. EP studies in this patient revealed no EP AChE, small nerve terminals, reduced presynaptic membrane length, as well as abnormally low-evoked quantal release. The third mutation (G240X) was homozygous in six Palestinian Arab families of the same tribe and in an Iraqi Jewish patient. Expression studies of the three mutations in COS cells indicate that each abrogates formation of insertion competent asymmetric AChE. Although the three mutations have identical predicted consequences at the EP, their phenotypic expressivity varies as regards age at onset, rate of progression, and severity of symptoms. Conclusions: 1) After mutations in the AChR e subunit, mutations in COLQ are emerging as second most common cause of congenital myasthenic syndromes. 2) A founder effect is likely for G240X in the Palestinian Arab families. 3) That mutations predicting total absence of AChE from the EP have variable phenotypic expressivity suggests that modifying genes or environmental factors can partially compensate for EP AChE deficiency.

Original languageEnglish (US)
Pages (from-to)603-609
Number of pages7
JournalNeurology
Volume58
Issue number4
StatePublished - Feb 26 2002

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Mutation
Acetylcholinesterase
COS Cells
Tail
Congenital Myasthenic Syndromes
Founder Effect
Presynaptic Terminals
Microelectrodes
Age of Onset
Population Groups
Basement Membrane
Catalytic Domain
Electron Microscopy
Immunohistochemistry
Membranes
Enzymes
Genes
Endplate Acetylcholinesterase Deficiency

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Shapira, Y. A., Sadeh, M. E., Bergtraum, M. P., Tsujino, A., Ohno, K., Shen, X. M., ... Engel, A. G. (2002). Three novel COLQ mutations and variation of phenotypic expressivity due to G240X. Neurology, 58(4), 603-609.

Three novel COLQ mutations and variation of phenotypic expressivity due to G240X. / Shapira, Y. A.; Sadeh, M. E.; Bergtraum, M. P.; Tsujino, A.; Ohno, K.; Shen, X. M.; Brengman, J.; Edwardson, S.; Matoth, I.; Engel, Andrew G.

In: Neurology, Vol. 58, No. 4, 26.02.2002, p. 603-609.

Research output: Contribution to journalArticle

Shapira, YA, Sadeh, ME, Bergtraum, MP, Tsujino, A, Ohno, K, Shen, XM, Brengman, J, Edwardson, S, Matoth, I & Engel, AG 2002, 'Three novel COLQ mutations and variation of phenotypic expressivity due to G240X', Neurology, vol. 58, no. 4, pp. 603-609.
Shapira YA, Sadeh ME, Bergtraum MP, Tsujino A, Ohno K, Shen XM et al. Three novel COLQ mutations and variation of phenotypic expressivity due to G240X. Neurology. 2002 Feb 26;58(4):603-609.
Shapira, Y. A. ; Sadeh, M. E. ; Bergtraum, M. P. ; Tsujino, A. ; Ohno, K. ; Shen, X. M. ; Brengman, J. ; Edwardson, S. ; Matoth, I. ; Engel, Andrew G. / Three novel COLQ mutations and variation of phenotypic expressivity due to G240X. In: Neurology. 2002 ; Vol. 58, No. 4. pp. 603-609.
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AU - Shapira, Y. A.

AU - Sadeh, M. E.

AU - Bergtraum, M. P.

AU - Tsujino, A.

AU - Ohno, K.

AU - Shen, X. M.

AU - Brengman, J.

AU - Edwardson, S.

AU - Matoth, I.

AU - Engel, Andrew G

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N2 - Objective: To determine the molecular basis and consequences of endplate (EP) acetylcholinesterase (AChE) deficiency. Background: The EP species AChE is an asymmetric enzyme consisting of a tail subunit composed of three collagenic strands (ColQ), each attached to a tetramer of catalytic subunits. The tail subunit is essential for insertion of AChE into the synaptic basal lamina. Human EP AChE deficiency is caused by mutations in COLQ. The authors report three novel COLQ mutations in eight kinships. Methods: Immunocytochemistry, electron microscopy, microelectrode recordings, mutation analysis, and expression studies in COS cells were employed. Results: Two mutations (275insC and Q211X) were heterozygous in one patient. EP studies in this patient revealed no EP AChE, small nerve terminals, reduced presynaptic membrane length, as well as abnormally low-evoked quantal release. The third mutation (G240X) was homozygous in six Palestinian Arab families of the same tribe and in an Iraqi Jewish patient. Expression studies of the three mutations in COS cells indicate that each abrogates formation of insertion competent asymmetric AChE. Although the three mutations have identical predicted consequences at the EP, their phenotypic expressivity varies as regards age at onset, rate of progression, and severity of symptoms. Conclusions: 1) After mutations in the AChR e subunit, mutations in COLQ are emerging as second most common cause of congenital myasthenic syndromes. 2) A founder effect is likely for G240X in the Palestinian Arab families. 3) That mutations predicting total absence of AChE from the EP have variable phenotypic expressivity suggests that modifying genes or environmental factors can partially compensate for EP AChE deficiency.

AB - Objective: To determine the molecular basis and consequences of endplate (EP) acetylcholinesterase (AChE) deficiency. Background: The EP species AChE is an asymmetric enzyme consisting of a tail subunit composed of three collagenic strands (ColQ), each attached to a tetramer of catalytic subunits. The tail subunit is essential for insertion of AChE into the synaptic basal lamina. Human EP AChE deficiency is caused by mutations in COLQ. The authors report three novel COLQ mutations in eight kinships. Methods: Immunocytochemistry, electron microscopy, microelectrode recordings, mutation analysis, and expression studies in COS cells were employed. Results: Two mutations (275insC and Q211X) were heterozygous in one patient. EP studies in this patient revealed no EP AChE, small nerve terminals, reduced presynaptic membrane length, as well as abnormally low-evoked quantal release. The third mutation (G240X) was homozygous in six Palestinian Arab families of the same tribe and in an Iraqi Jewish patient. Expression studies of the three mutations in COS cells indicate that each abrogates formation of insertion competent asymmetric AChE. Although the three mutations have identical predicted consequences at the EP, their phenotypic expressivity varies as regards age at onset, rate of progression, and severity of symptoms. Conclusions: 1) After mutations in the AChR e subunit, mutations in COLQ are emerging as second most common cause of congenital myasthenic syndromes. 2) A founder effect is likely for G240X in the Palestinian Arab families. 3) That mutations predicting total absence of AChE from the EP have variable phenotypic expressivity suggests that modifying genes or environmental factors can partially compensate for EP AChE deficiency.

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