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The Journal of Neuroscience, December 26, 2007, 27(52):14515-14524; doi:10.1523/JNEUROSCI.4338-07.2007

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Neurobiology of Disease
Proprioceptive Sensory Neuropathy in Mice with a Mutation in the Cytoplasmic Dynein Heavy Chain 1 Gene

Xiang-Jun Chen,^1,2 Eleni N. Levedakou,^1,2 Kathleen J. Millen,⁴ Robert L. Wollmann,^1,2,3 Betty Soliven,^1,2 and Brian Popko^1,2

¹Jack Miller Center for Peripheral Neuropathy and Departments of ²Neurology, ³Pathology, and ⁴Human Genetics, The University of Chicago, Chicago, Illinois 60637

Correspondence should be addressed to Brian Popko, Jack Miller Center for Peripheral Neuropathy, Department of Neurology, The University of Chicago, 5841 South Maryland Avenue, MC 2030, Chicago, IL 60637. Email: bpopko{at}uchicago.edu

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.

Key words: Charcot-Marie-Tooth disease; dynein; sensory neuron degeneration; dorsal root ganglia; gene deletion; mouse mutant

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Received Sept. 21, 2007; revised Oct. 26, 2007; accepted Oct. 27, 2007.

Correspondence should be addressed to Brian Popko, Jack Miller Center for Peripheral Neuropathy, Department of Neurology, The University of Chicago, 5841 South Maryland Avenue, MC 2030, Chicago, IL 60637. Email: bpopko{at}uchicago.edu

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