Mutation causing congenital myasthenia reveals acetylcholine receptor β/δ subunit interaction essential for assembly

Polly A. Quiram, Kinji Ohno, Margherita Milone, Marc C. Patterson, Ned J. Pruitt, Joan M. Brengman, Steven M Sine, Andrew G Engel

Research output: Contribution to journalArticle

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Abstract

We describe a severe postsynaptic congenital myasthenic syndrome with marked endplate acetylcholine receptor (AChR) deficiency caused by 2 heteroallelic mutations in the β subunit gene. One mutation causes skipping of exon 8,truncating the β subunit before its M1 transmembrane domain, and abolishing surface expression of pentameric AChR. The other mutation, a 3- codon deletion (β426delEQE) in the long cytoplasmic loop between the M3 and M4 domains, curtails but does not abolish expression. By coexpressing β426delEQE with combinations of wild-type subunits in 293 HEK cells, we demonstrate that β426delEQE impairs AChR assembly by disrupting a specific interaction between β and δ subunits. Studies with related deletion and missense mutants indicate that secondary structure in this region of the β subunit is crucial for interaction with the δ subunit. The findings imply that the mutated residues are positioned at the interface between β and δ subunits and demonstrate contribution of this local region of the long cytoplasmic loop to AChR assembly.

Original languageEnglish (US)
Pages (from-to)1403-1410
Number of pages8
JournalJournal of Clinical Investigation
Volume104
Issue number10
StatePublished - Nov 1999

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Congenital Myasthenic Syndromes
Cholinergic Receptors
Mutation
HEK293 Cells
Codon
Exons
Genes

ASJC Scopus subject areas

  • Medicine(all)

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Mutation causing congenital myasthenia reveals acetylcholine receptor β/δ subunit interaction essential for assembly. / Quiram, Polly A.; Ohno, Kinji; Milone, Margherita; Patterson, Marc C.; Pruitt, Ned J.; Brengman, Joan M.; Sine, Steven M; Engel, Andrew G.

In: Journal of Clinical Investigation, Vol. 104, No. 10, 11.1999, p. 1403-1410.

Research output: Contribution to journalArticle

Quiram, Polly A. ; Ohno, Kinji ; Milone, Margherita ; Patterson, Marc C. ; Pruitt, Ned J. ; Brengman, Joan M. ; Sine, Steven M ; Engel, Andrew G. / Mutation causing congenital myasthenia reveals acetylcholine receptor β/δ subunit interaction essential for assembly. In: Journal of Clinical Investigation. 1999 ; Vol. 104, No. 10. pp. 1403-1410.
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AU - Sine, Steven M

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