Myasthenic syndromes in Turkish kinships due to mutations in the acetylcholine receptor

Ohno, Kinji; Anlar, Banu; Ozdirim, E; Brengman, Joan M.; DeBleecker, Jan L.; Engel, Andrew G.

doi:10.1002/ana.410440214

Cited by 73 publications

(38 citation statements)

References 39 publications

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“…It is now known, however, that some CMSs are endemic in the Near East, where closed communities and consanguineous marriages are relatively frequent. 16,17 Table 2 lists clinical clues to the generic and specific diagnoses of the CMSs. However, in some patients there are no clinical clues that point to a specific type of CMS.…”

Section: Epidemiologymentioning

confidence: 99%

The Therapy of Congenital Myasthenic Syndromes

Engel

2007

Neurotherapeutics

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104

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Section: Epidemiologymentioning

confidence: 99%

The Therapy of Congenital Myasthenic Syndromes

Engel

2007

Neurotherapeutics

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104

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“…On the other hand, recessive lossof-function mutations reduce affinity for ACh, disturb the gating mechanism, or reduce AChR expression. Marked decrease of AChR expression is caused by mutations in AChR subunit genes that prematurely terminate the translational chain (17,(26)(27)(28), alter the signal peptide region (16), or affect residues essential for assembly of the pentameric receptor (16,26,29). Most of these mutations occur in the ε subunit gene, because compensatory expression of the fetal-type AChR that harbors the γ instead of the ε subunit (γ-AChR) may rescue the phenotype (26,27,29).…”

Section: Discussionmentioning

confidence: 99%

“…Human AChR α, β, δ, and ε subunit cDNA were cloned into the CMV-based expression vector pRBG4, as described elsewhere (16). The β1276del9 mutation, skipping of β exon 8, and the other artificial mutations were introduced into the β subunit cDNA in pRBG4 by the QuickChange Site-Directed Mutagenesis kit (Stratagene, La Jolla, California, USA) or by its megaprimer-based modification (17). Human embryonic kidney (HEK) 293 cells were transfected with AChR subunit cDNAs using calcium phosphate precipitation (16).…”

Section: Methodsmentioning

confidence: 99%

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

Quiram¹,

Ohno²,

Milone³

et al. 1999

J. Clin. Invest.

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The protein sequence of ion channels governs not only their ultimate function, but also encodes instructions for their correct assembly. Converting the linear peptide into the mature protein requires correct folding, posttranslational modification, and, for most ion channels, oligomerization (1). For the acetylcholine receptor (AChR) at the motor endplate (EP), these steps likely depend on local sequences in many parts of its α, β, ε, and δ subunits. Identifying such key assembly sequences typically relies on mutating residues conserved across the AChR superfamily. However, by identifying the genetic defects underlying a congenital myasthenic syndrome (CMS), the present work reveals a region of the AChR β subunit essential for assembly.The amino-terminal, extracellular half of each AChR subunit is widely recognized to mediate its initial association leading to the assembled pentamer (2, 3). A cystine loop within the extracellular domain, formed between C128 and C142 in all AChR subunits, has drawn considerable attention regarding its role in contributing to assembly. Formation of cystine loops in both α and β subunits is required for specific conformational changes and subunit oligomerization steps at intermediate stages of assembly (4). Furthermore, specific residues preceding the cystine loop affect assembly efficiency (5), whereas residues following the loop govern subunit specificity of oligomerization (6). On the other hand, residues in the M1 and M2 transmembrane domains are essential for assembly of homomeric versus heteromeric AChRs (7).We now uncover an additional domain essential for AChR assembly by identifying and characterizing the molecular defects that cause a severe CMS associated with marked EP-AChR deficiency. The deficiency arises from 2 heteroallelic recessive mutations in the β subunit. One causes skipping of exon 8, which abolishes expression of pentameric AChR; the second is a 3-codon deletion (β426delEQE) in the long cytoplasmic loop between transmembrane domains M3 and M4, which severely curtails expression of cell-surface AChR. By coexpressing β426delEQE and related deletion mutants with combinations of wild-type subunits, we demonstrate that β426delEQE impairs AChR assembly by disrupting a specific interaction between β and δ subunits. MethodsMuscle specimens. Intercostal muscle specimens were obtained intact from origin to insertion from the patient and control subjects without muscle disease undergoing thoracic surgery. A limb-muscle specimen was obtained from the patient's mother. All human studies were in accord with the guidelines of the Institutional Review Board of the Mayo Clinic.AChR and acetylcholinesterase (AChE) were localized in cryostat sections by 2-color fluorescence (8). EPs were localized for electron microscopy (9) and quantitatively analyzed (10) 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 exo...

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“…For example, ɛIVS6+1G>T at the 5' splice site of CHRNE intron 6 causes skipping of exon 6 ( Figure 2b) [9]. Another 5' splice site mutation, ɛIVS7+2T>C in CHRNE intron 7, causes retention of intron 7 [10]. On the other hand, ɛIVS9-1G>C at the 3' splice site of CHRNE intron 9 causes retention of intron 9, and subsequently generates a PTC in exon 10 in the final transcript [11].…”

Section: Mutations Affecting the Consensus Splicing Cis-elementsmentioning

confidence: 99%