Mutations in Different Functional Domains of the Human Muscle Acetylcholine Receptor Subunit in Patients with the Slow-Channel congenital Myasthenic Syndrome
| Autor: | Claire Newland, Guy Chauplannaz, John Newsom-Davis, Angela Vincent, Hans Oosterhuis, David Beeson, R Croxen |
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| Rok vydání: | 1997 |
| Předmět: |
Adult
Male Heterozygote medicine.medical_specialty Patch-Clamp Techniques Adolescent Xenopus Molecular Sequence Data Neuromuscular transmission Alpha (ethology) Biology Transfection medicine.disease_cause Pregnancy Internal medicine Myasthenia Gravis Genetics medicine Animals Humans Receptors Cholinergic Amino Acid Sequence Hyperekplexia Molecular Biology Polymorphism Single-Stranded Conformational Genetics (clinical) Ion channel G alpha subunit Acetylcholine receptor Mutation Binding Sites Sequence Homology Amino Acid Muscles Sequence Analysis DNA General Medicine Middle Aged Congenital myasthenic syndrome medicine.disease Recombinant Proteins Cell biology Electrophysiology Endocrinology Oocytes Female medicine.symptom |
| Zdroj: | Human Molecular Genetics. 6:767-774 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/6.5.767 |
| Popis: | Congenital myasthenic syndromes are a group of rare genetic disorders that compromise neuromuscular transmission. A subset of these disorders, the slow-channel congenital myasthenic syndrome (SCCMS), is dominantly inherited and has been shown to involve mutations within the muscle acetylcholine receptor (AChR). We have identified three new SCCMS mutations and a further familial case of the alpha G153S mutation. Single channel recordings from wild-type and mutant human AChR expressed in Xenopus oocytes demonstrate that each mutation prolongs channel activation episodes. The novel mutations alpha V156M, alpha T254I and alpha S269I are in different functional domains of the AChR alpha subunit. Whereas alpha T254I is in the pore-lining region, like five of six previously reported SCCMS mutations, alpha S269I and alpha V156M are in extracellular domains. alpha S269I lies within the short extracellular sequence between M2 and M3, and identifies a new region of muscle AChR involved in ACh binding/channel gating. alpha V156M, although located close to alpha G153S which has been shown to increase ACh binding affinity, appears to alter channel function through a different molecular mechanism. Our results demonstrate heterogeneity in the SCCMS, indicate new regions of the AChR involved in ACh binding/channel gating and highlight the potential role of mutations outside the pore-lining regions in altering channel function in other ion channel disorders. |
| Databáze: | OpenAIRE |
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