title: Proprioceptive sensory neuropathy in mice with a mutation in the cytoplasmic Dynein heavy chain 1 gene.
abstract: Mice heterozygous for the radiation-induced Sprawling (Swl) mutation display an early-onset sensory neuropathy with muscle spindle deficiency. The lack of an H reflex despite normal motor nerve function in the hindlimbs of these mutants strongly suggests defective proprioception. Immunohistochemical analyses reveal that proprioceptive sensory neurons are severely compromised in the lumbar dorsal root ganglia of newborn Swl/+ mice, whereas motor neuron numbers remain unaltered even in aged animals. We have used positional cloning to identify a nine base-pair deletion in the cytoplasmic dynein heavy chain 1 gene (Dync1h1) in this mutant. Furthermore, we demonstrate that Loa/+ mice, which have previously been shown to carry a missense point mutation in Dync1h1 that results in late-onset motor neuron loss, also present with a severe, early-onset proprioceptive sensory neuropathy. Interestingly, in contrast to the Loa mutation, the Swl mutation does not delay disease progression in a motor neuron disease mouse model overexpressing a human mutant superoxide dismutase (SOD1(G93A)) transgene. Together, we provide in vivo evidence that distinct mutations in cytoplasmic dynein can either result in a pure sensory neuropathy or in a sensory neuropathy with motor neuron involvement.
authors.affiliation: Jack Miller Center for Peripheral Neuropathy and Department of Neurology, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Xiang-Jun
authors.initials: XJ
authors.lastname: Chen
authors.forename: Eleni N
authors.initials: EN
authors.lastname: Levedakou
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Millen
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wollmann
authors.forename: Betty
authors.initials: B
authors.lastname: Soliven
authors.forename: Brian
authors.initials: B
authors.lastname: Popko
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology; D002452:Cell Count / Q000379:methods; D024141:Collagen Type IV / Q000378:metabolism; D056445:Cytoplasmic Dyneins; D004195:Disease Models, Animal; D004398:Dyneins / Q000235:genetics*; D004622:Embryo, Mammalian; D005727:Ganglia, Spinal / Q000473:pathology; D006181:H-Reflex / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009470:Muscle Spindles / Q000196:embryology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009431:Neural Conduction / Q000235:genetics; D009474:Neurons / Q000502:physiology; D011597:Psychomotor Performance / Q000502:physiology; D020886:Somatosensory Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*
chemical_list: D024141:Collagen Type IV; C516947:Dync1h1 protein, mouse; D009419:Nerve Tissue Proteins; D056445:Cytoplasmic Dyneins; D004398:Dyneins