Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor ε-subunit gene

L. Middleton, K. Ohno, K. Christodoulou, J. Brengman, Margherita Milone, V. Neocleous, P. Serdaroǧlu, F. Deymeer, C. Özdemir, A. Mubaidin, K. Horany, A. Al-Shehab, I. Mavromatis, I. Mylonas, M. Tsingis, E. Zamba, M. Pantzaris, K. Kyriallis, Andrew G Engel

Research output: Contribution to journalArticle

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Abstract

Objective: To identify and to characterize functionally the mutational basis of congenital myasthenic syndromes (CMS) linked to chromosome 17p. Background: A total of 37 patients belonging to 13 CMS families, 9 of them consanguineous, were investigated. All patients were linked previously to the telomeric region of chromosome 17p. Two candidate genes in this region encode synaptobrevin 2, a presynaptic protein, and the ε-subunit of the acetylcholine receptor (AChR). Direct sequencing of the synaptobrevin 2 gene revealed no mutations. The authors thus searched for mutations in the ε- subunit gene of AChR. Methods: Direct sequencing of the AChR ε-subunit, restriction analysis, allele-specific PCR, and expression studies in human embryonic kidney cells were performed. Results: The authors identified two previously characterized and five novel ε-subunit gene mutations, all homozygous, in the 13 kinships. Two of the novel mutations are truncating (ε723delC and ε760ins8), one is a missense mutation in the signal peptide region (εV-13D), one is a missense mutation in the N-terminal extracellular domain (εT51P), and one is a splice donor site mutation in intron 10 (εIVS10+2T→G). Unaffected family members have no mutations or are heterozygous. Expression studies indicate that the four novel mutations in the coding region of the gene and the most likely transcript of the splice- site mutation, which skips exon 10, are low-expressor or null mutations. Conclusions: Chromosome 17p-linked congenital myasthenic syndromes are caused by low-expressor/null mutations in the AChR ε-subunit gene. Mutations in this gene are a common cause of CMS in eastern Mediterranean countries.

Original languageEnglish (US)
Pages (from-to)1076-1082
Number of pages7
JournalNeurology
Volume53
Issue number5
StatePublished - Sep 22 1999

Fingerprint

Cholinergic Receptors
Chromosomes
Mutation
Congenital Myasthenic Syndromes
Genes
Vesicle-Associated Membrane Protein 2
Missense Mutation
RNA Splice Sites
Protein Subunits
Protein Sorting Signals
Introns
Exons
Alleles
Kidney
Polymerase Chain Reaction

Keywords

  • Acetylcholine receptor
  • Chromosome 17p
  • Congenital myasthenic syndromes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Middleton, L., Ohno, K., Christodoulou, K., Brengman, J., Milone, M., Neocleous, V., ... Engel, A. G. (1999). Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor ε-subunit gene. Neurology, 53(5), 1076-1082.

Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor ε-subunit gene. / Middleton, L.; Ohno, K.; Christodoulou, K.; Brengman, J.; Milone, Margherita; Neocleous, V.; Serdaroǧlu, P.; Deymeer, F.; Özdemir, C.; Mubaidin, A.; Horany, K.; Al-Shehab, A.; Mavromatis, I.; Mylonas, I.; Tsingis, M.; Zamba, E.; Pantzaris, M.; Kyriallis, K.; Engel, Andrew G.

In: Neurology, Vol. 53, No. 5, 22.09.1999, p. 1076-1082.

Research output: Contribution to journalArticle

Middleton, L, Ohno, K, Christodoulou, K, Brengman, J, Milone, M, Neocleous, V, Serdaroǧlu, P, Deymeer, F, Özdemir, C, Mubaidin, A, Horany, K, Al-Shehab, A, Mavromatis, I, Mylonas, I, Tsingis, M, Zamba, E, Pantzaris, M, Kyriallis, K & Engel, AG 1999, 'Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor ε-subunit gene', Neurology, vol. 53, no. 5, pp. 1076-1082.
Middleton L, Ohno K, Christodoulou K, Brengman J, Milone M, Neocleous V et al. Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor ε-subunit gene. Neurology. 1999 Sep 22;53(5):1076-1082.
Middleton, L. ; Ohno, K. ; Christodoulou, K. ; Brengman, J. ; Milone, Margherita ; Neocleous, V. ; Serdaroǧlu, P. ; Deymeer, F. ; Özdemir, C. ; Mubaidin, A. ; Horany, K. ; Al-Shehab, A. ; Mavromatis, I. ; Mylonas, I. ; Tsingis, M. ; Zamba, E. ; Pantzaris, M. ; Kyriallis, K. ; Engel, Andrew G. / Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor ε-subunit gene. In: Neurology. 1999 ; Vol. 53, No. 5. pp. 1076-1082.
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abstract = "Objective: To identify and to characterize functionally the mutational basis of congenital myasthenic syndromes (CMS) linked to chromosome 17p. Background: A total of 37 patients belonging to 13 CMS families, 9 of them consanguineous, were investigated. All patients were linked previously to the telomeric region of chromosome 17p. Two candidate genes in this region encode synaptobrevin 2, a presynaptic protein, and the ε-subunit of the acetylcholine receptor (AChR). Direct sequencing of the synaptobrevin 2 gene revealed no mutations. The authors thus searched for mutations in the ε- subunit gene of AChR. Methods: Direct sequencing of the AChR ε-subunit, restriction analysis, allele-specific PCR, and expression studies in human embryonic kidney cells were performed. Results: The authors identified two previously characterized and five novel ε-subunit gene mutations, all homozygous, in the 13 kinships. Two of the novel mutations are truncating (ε723delC and ε760ins8), one is a missense mutation in the signal peptide region (εV-13D), one is a missense mutation in the N-terminal extracellular domain (εT51P), and one is a splice donor site mutation in intron 10 (εIVS10+2T→G). Unaffected family members have no mutations or are heterozygous. Expression studies indicate that the four novel mutations in the coding region of the gene and the most likely transcript of the splice- site mutation, which skips exon 10, are low-expressor or null mutations. Conclusions: Chromosome 17p-linked congenital myasthenic syndromes are caused by low-expressor/null mutations in the AChR ε-subunit gene. Mutations in this gene are a common cause of CMS in eastern Mediterranean countries.",
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T1 - Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor ε-subunit gene

AU - Middleton, L.

AU - Ohno, K.

AU - Christodoulou, K.

AU - Brengman, J.

AU - Milone, Margherita

AU - Neocleous, V.

AU - Serdaroǧlu, P.

AU - Deymeer, F.

AU - Özdemir, C.

AU - Mubaidin, A.

AU - Horany, K.

AU - Al-Shehab, A.

AU - Mavromatis, I.

AU - Mylonas, I.

AU - Tsingis, M.

AU - Zamba, E.

AU - Pantzaris, M.

AU - Kyriallis, K.

AU - Engel, Andrew G

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N2 - Objective: To identify and to characterize functionally the mutational basis of congenital myasthenic syndromes (CMS) linked to chromosome 17p. Background: A total of 37 patients belonging to 13 CMS families, 9 of them consanguineous, were investigated. All patients were linked previously to the telomeric region of chromosome 17p. Two candidate genes in this region encode synaptobrevin 2, a presynaptic protein, and the ε-subunit of the acetylcholine receptor (AChR). Direct sequencing of the synaptobrevin 2 gene revealed no mutations. The authors thus searched for mutations in the ε- subunit gene of AChR. Methods: Direct sequencing of the AChR ε-subunit, restriction analysis, allele-specific PCR, and expression studies in human embryonic kidney cells were performed. Results: The authors identified two previously characterized and five novel ε-subunit gene mutations, all homozygous, in the 13 kinships. Two of the novel mutations are truncating (ε723delC and ε760ins8), one is a missense mutation in the signal peptide region (εV-13D), one is a missense mutation in the N-terminal extracellular domain (εT51P), and one is a splice donor site mutation in intron 10 (εIVS10+2T→G). Unaffected family members have no mutations or are heterozygous. Expression studies indicate that the four novel mutations in the coding region of the gene and the most likely transcript of the splice- site mutation, which skips exon 10, are low-expressor or null mutations. Conclusions: Chromosome 17p-linked congenital myasthenic syndromes are caused by low-expressor/null mutations in the AChR ε-subunit gene. Mutations in this gene are a common cause of CMS in eastern Mediterranean countries.

AB - Objective: To identify and to characterize functionally the mutational basis of congenital myasthenic syndromes (CMS) linked to chromosome 17p. Background: A total of 37 patients belonging to 13 CMS families, 9 of them consanguineous, were investigated. All patients were linked previously to the telomeric region of chromosome 17p. Two candidate genes in this region encode synaptobrevin 2, a presynaptic protein, and the ε-subunit of the acetylcholine receptor (AChR). Direct sequencing of the synaptobrevin 2 gene revealed no mutations. The authors thus searched for mutations in the ε- subunit gene of AChR. Methods: Direct sequencing of the AChR ε-subunit, restriction analysis, allele-specific PCR, and expression studies in human embryonic kidney cells were performed. Results: The authors identified two previously characterized and five novel ε-subunit gene mutations, all homozygous, in the 13 kinships. Two of the novel mutations are truncating (ε723delC and ε760ins8), one is a missense mutation in the signal peptide region (εV-13D), one is a missense mutation in the N-terminal extracellular domain (εT51P), and one is a splice donor site mutation in intron 10 (εIVS10+2T→G). Unaffected family members have no mutations or are heterozygous. Expression studies indicate that the four novel mutations in the coding region of the gene and the most likely transcript of the splice- site mutation, which skips exon 10, are low-expressor or null mutations. Conclusions: Chromosome 17p-linked congenital myasthenic syndromes are caused by low-expressor/null mutations in the AChR ε-subunit gene. Mutations in this gene are a common cause of CMS in eastern Mediterranean countries.

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