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

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

From the Cyprus Institute of Neurology and Genetics (Drs. Middleton, Christodoulou, Neocleous, Zamba, Pantzaris, Kyriallis, and Tsingis), Nicosia, Cyprus; the Department of Neurology and Neuromuscular Research Laboratory (Drs. Ohno, Milone, and Engel, and J. Brengman), Mayo Clinic, Rochester, MN; the Department of Neurology (Drs. Deymeer, Serdarolu, and Özdemir), Istanbul University, Turkey; King Hussein Medical Center (Drs. Mubaidin and Horany), Amman, Jordan; the Faculty of Medicine (Dr. Al-Shebab), University of Jordan, Amman, Jordan; and the Neurology Clinic (Drs. Mavromatis and Mylonas), Aristotelion University, Thessaloniki, Greece.

Address correspondence and reprint requests to Dr. A.G. Engel, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.

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 -subunit of the acetylcholine receptor (AChR). Direct sequencing of the synaptobrevin 2 gene revealed no mutations. The authors thus searched for mutations in the -subunit gene of AChR.

METHODS: Direct sequencing of the AChR -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 -subunit gene mutations, all homozygous, in the 13 kinships. Two of the novel mutations are truncating (723delC and 760ins8), one is a missense mutation in the signal peptide region (V-13D), one is a missense mutation in the N-terminal extracellular domain (T51P), and one is a splice donor site mutation in intron 10 (IVS10+2TG). 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 -subunit gene. Mutations in this gene are a common cause of CMS in eastern Mediterranean countries.

Key words: Congenital myasthenic syndromes—Chromosome 17p—Acetylcholine receptor.

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