title: Lack of neuropathy-related phenotypes in hint1 knockout mice.
abstract: Mutations in HINT1, the gene encoding histidine triad nucleotide-binding protein 1 (HINT1), cause a recessively inherited peripheral neuropathy that primarily involves motor dysfunction and is usually associated with neuromyotonia (i.e. prolonged muscle contraction resulting from hyperexcitability of peripheral nerves). Because these mutations are hypothesized to cause loss of function, we analyzed Hint1 knockout mice for their relevance as a disease model. Mice lacking Hint1 appeared normal and yielded normal behavioral test results or motor performance, although they moved more slowly and for a smaller fraction of time in an open-field arena than wild-type mice. Muscles, neuromuscular junctions, and nodes of Ranvier were anatomically normal and did not show evidence of degeneration or regeneration. Axon numbers and myelination in peripheral nerves were normal at ages 4 and 13 months. Axons were slightly smaller than those in wild-type mice at age 4 months, but this did not cause a decrease in conduction velocity, and no differences in axon diameters were detected at 13 months. With electromyography, we were unable to detect neuromyotonia even after using supraphysiologic stimuli and stressors such as reduced temperature or 3,4-diaminopyridine to block potassium channels. Therefore, we conclude that Hint1 knockout mice may be useful for studying the biochemical activities of HINT1, but these mice do not provide a disease model or a means for investigating the basis of HINT1-associated neuropathy and neuromyotonia.
authors.affiliation: From The Jackson Laboratory, Bar Harbor (KLS, KHM, RWB); Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono (KHM, RWB), Maine; and Vlaams Instituut voor Biotechnologie Department of Molecular Genetics (AJ) and Neurogenetics Laboratory, Institute Born-Bunge (AJ), University of Antwerp, Antwerp, Belgium.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Seburn
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Morelli
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.forename: Robert W
authors.initials: RW
authors.lastname: Burgess
mesh_terms: D015761:4-Aminopyridine / Q000031:analogs & derivatives; D000077770:Amifampridine; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000523:psychology; D001369:Axons / Q000648:ultrastructure; D001522:Behavior, Animal / Q000502:physiology; D004576:Electromyography; D007150:Immunohistochemistry; D020386:Isaacs Syndrome / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D018482:Muscle, Skeletal / Q000294:innervation / Q000473:pathology; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D004856:Postural Balance / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011597:Psychomotor Performance / Q000502:physiology
chemical_list: C489275:Hint1 protein, mouse; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D015761:4-Aminopyridine; D000077770:Amifampridine