title: A single mutation in the acetylcholine receptor δ-subunit causes distinct effects in two types of neuromuscular synapses.
abstract: Mutations in AChR subunits, expressed as pentamers in neuromuscular junctions (NMJs), cause various types of congenital myasthenic syndromes. In AChR pentamers, the adult ε subunit gradually replaces the embryonic γ subunit as the animal develops. Because of this switch in subunit composition, mutations in specific subunits result in synaptic phenotypes that change with developmental age. However, a mutation in any AChR subunit is considered to affect the NMJs of all muscle fibers equally. Here, we report a zebrafish mutant of the AChR δ subunit that exhibits two distinct NMJ phenotypes specific to two muscle fiber types: slow or fast. Homozygous fish harboring a point mutation in the δ subunit form functional AChRs in slow muscles, whereas receptors in fast muscles are nonfunctional. To test the hypothesis that different subunit compositions in slow and fast muscles underlie distinct phenotypes, we examined the presence of ε/γ subunits in NMJs using specific antibodies. Both wild-type and mutant larvae lacked ε/γ subunits in slow muscle synapses. These findings in zebrafish suggest that some mutations in human congenital myasthenic syndromes may affect slow and fast muscle fibers differently.
authors: Section on Model Synaptic Systems, Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892.
authors: Jee-Young
authors: JY
authors: Park
authors: Section on Model Synaptic Systems, Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892.
authors: Meghan
authors: M
authors: Mott
authors: Section on Model Synaptic Systems, Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892.
authors: Tory
authors: T
authors: Williams
authors: Section on Model Synaptic Systems, Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892.
authors: Hiromi
authors: H
authors: Ikeda
authors: Oregon Health and Science University, Portland, Oregon 97239, and.
authors: Hua
authors: H
authors: Wen
authors: Oregon Health and Science University, Portland, Oregon 97239, and.
authors: Michael
authors: M
authors: Linhoff
authors: Section on Model Synaptic Systems, Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, Department of Physiology, Osaka Medical College, Takatsuki, Japan, 569-0801 onof@mail.nih.gov.
authors: Fumihito
authors: F
authors: Ono
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D019274:Botulinum Toxins, Type A / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007814:Larva; D007930:Leucine / Q000235:genetics; D008124:Locomotion / Q000235:genetics; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009469:Neuromuscular Junction / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011392:Proline / Q000235:genetics; D011950:Receptors, Cholinergic / Q000235:genetics*; D013550:Swimming / Q000502:physiology; D015027:Zebrafish
chemical_list: C514767:CHRND protein, human; D011950:Receptors, Cholinergic; D049452:Green Fluorescent Proteins; D011392:Proline; D019274:Botulinum Toxins, Type A; D007930:Leucine; D000109:Acetylcholine
keywords: acetylcholine receptors; neuromuscular diseases; zebrafish