title: Hcn1 is a tremorgenic genetic component in a rat model of essential tremor.
abstract: Genetic factors are thought to play a major role in the etiology of essential tremor (ET); however, few genetic changes that induce ET have been identified to date. In the present study, to find genes responsible for the development of ET, we employed a rat model system consisting of a tremulous mutant strain, TRM/Kyo (TRM), and its substrain TRMR/Kyo (TRMR). The TRM rat is homozygous for the tremor (tm) mutation and shows spontaneous tremors resembling human ET. The TRMR rat also carries a homozygous tm mutation but shows no tremor, leading us to hypothesize that TRM rats carry one or more genes implicated in the development of ET in addition to the tm mutation. We used a positional cloning approach and found a missense mutation (c. 1061 C>T, p. A354V) in the hyperpolarization-activated cyclic nucleotide-gated 1 channel (Hcn1) gene. The A354V HCN1 failed to conduct hyperpolarization-activated currents in vitro, implicating it as a loss-of-function mutation. Blocking HCN1 channels with ZD7288 in vivo evoked kinetic tremors in nontremulous TRMR rats. We also found neuronal activation of the inferior olive (IO) in both ZD7288-treated TRMR and non-treated TRM rats and a reduced incidence of tremor in the IO-lesioned TRM rats, suggesting a critical role of the IO in tremorgenesis. A rat strain carrying the A354V mutation alone on a genetic background identical to that of the TRM rats showed no tremor. Together, these data indicate that body tremors emerge when the two mutant loci, tm and Hcn1A354V, are combined in a rat model of ET. In this model, HCN1 channels play an important role in the tremorgenesis of ET. We propose that oligogenic, most probably digenic, inheritance is responsible for the genetic heterogeneity of ET.
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, 569-1094, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Ohno
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, 569-1094, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, 569-1094, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Tatara
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, 569-1094, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Imaoku
authors.affiliation: Department of Physiology and Neurobiology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Nagisa Clinic, Hirakata, Osaka, 573-1183, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sasa
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, 569-1094, Japan; Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Serikawa
authors.affiliation: Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuramoto
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D020329:Essential Tremor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D018740:Genetic Heterogeneity; D056426:Genetic Loci; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D040582:Inheritance Patterns; D020125:Mutation, Missense; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D055647:Rats, Transgenic; D015398:Signal Transduction; D013238:Stereotaxic Techniques; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: C578667:Hcn1 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D016760:Proto-Oncogene Proteins c-fos; D011743:Pyrimidines; C082246:ICI D2788