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Hcn1 is a tremorgenic genetic component in a rat model of essential tremor.

Ohno Y, Shimizu S, Tatara A, Imaoku T, Ishii T, Sasa M, Serikawa T, Kuramoto T - PLoS ONE (2015)

Bottom Line: We used a positional cloning approach and found a missense mutation (c. 1061 C>T, p.The A354V HCN1 failed to conduct hyperpolarization-activated currents in vitro, implicating it as a loss-of-function mutation.We propose that oligogenic, most probably digenic, inheritance is responsible for the genetic heterogeneity of ET.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, 569-1094, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

Tremor induction by the HCN1 channel blocker ZD7288 in TRMR rats.A: Genetic components responsible for tremor development in our rat model of ET. TRM rats, carrying both the tm deletion (red) and the Hcn1 mutation (blue), showed body tremors. TRMR rats, carrying the tm deletion but not the Hcn1 mutation, showed no body tremors, but body tremors were induced when the selective HCN1 channel blocker ZD7288 was administered (see B, this figure). WTC rats, carrying the Hcn1 mutation but not the tm deletion, showed no body tremors with or without administration of ZD7288 (see B, this figure). B: Effects of ZD7288 on tremor induction in nontremulous TRMR rats. Duration and intensity of tremor observed in TRMR rats that received vehicle or ZD7288. Data are presented as the mean ± SEM of seven (vehicle) or eight (ZD7288) animals. *P<0.05, **P<0.01 vs. pre-treatment control levels (pre).
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pone.0123529.g004: Tremor induction by the HCN1 channel blocker ZD7288 in TRMR rats.A: Genetic components responsible for tremor development in our rat model of ET. TRM rats, carrying both the tm deletion (red) and the Hcn1 mutation (blue), showed body tremors. TRMR rats, carrying the tm deletion but not the Hcn1 mutation, showed no body tremors, but body tremors were induced when the selective HCN1 channel blocker ZD7288 was administered (see B, this figure). WTC rats, carrying the Hcn1 mutation but not the tm deletion, showed no body tremors with or without administration of ZD7288 (see B, this figure). B: Effects of ZD7288 on tremor induction in nontremulous TRMR rats. Duration and intensity of tremor observed in TRMR rats that received vehicle or ZD7288. Data are presented as the mean ± SEM of seven (vehicle) or eight (ZD7288) animals. *P<0.05, **P<0.01 vs. pre-treatment control levels (pre).

Mentions: To determine whether HCN1 channel dysfunction is responsible for the generation of tremors in vivo, we evaluated the actions of a selective HCN1 channel blocker, ZD7288, in nontremulous TRMR and WTC rats, which carry the tm deletion or not, respectively, on identical genetic backgrounds (Fig 4A). When ZD7288 (30 μg/rat) was microinjected into the LV, intensive body tremors were evoked in all TRMR rats, but in none of the WTC rats (Fig 4B). The clinical manifestation of the induced tremor was comparable with that of the TRM rats and significant increases in the duration and intensity of the tremor persisted during the 4 h observation period (intensity: P = 0.0014; duration: P = 0.0025). Vehicle alone did not induce tremors in the TRMR rats. This result clearly demonstrates that Hcn1 is the gene responsible for tremors (trm2) in our rat model of ET.


Hcn1 is a tremorgenic genetic component in a rat model of essential tremor.

Ohno Y, Shimizu S, Tatara A, Imaoku T, Ishii T, Sasa M, Serikawa T, Kuramoto T - PLoS ONE (2015)

Tremor induction by the HCN1 channel blocker ZD7288 in TRMR rats.A: Genetic components responsible for tremor development in our rat model of ET. TRM rats, carrying both the tm deletion (red) and the Hcn1 mutation (blue), showed body tremors. TRMR rats, carrying the tm deletion but not the Hcn1 mutation, showed no body tremors, but body tremors were induced when the selective HCN1 channel blocker ZD7288 was administered (see B, this figure). WTC rats, carrying the Hcn1 mutation but not the tm deletion, showed no body tremors with or without administration of ZD7288 (see B, this figure). B: Effects of ZD7288 on tremor induction in nontremulous TRMR rats. Duration and intensity of tremor observed in TRMR rats that received vehicle or ZD7288. Data are presented as the mean ± SEM of seven (vehicle) or eight (ZD7288) animals. *P<0.05, **P<0.01 vs. pre-treatment control levels (pre).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4430019&req=5

pone.0123529.g004: Tremor induction by the HCN1 channel blocker ZD7288 in TRMR rats.A: Genetic components responsible for tremor development in our rat model of ET. TRM rats, carrying both the tm deletion (red) and the Hcn1 mutation (blue), showed body tremors. TRMR rats, carrying the tm deletion but not the Hcn1 mutation, showed no body tremors, but body tremors were induced when the selective HCN1 channel blocker ZD7288 was administered (see B, this figure). WTC rats, carrying the Hcn1 mutation but not the tm deletion, showed no body tremors with or without administration of ZD7288 (see B, this figure). B: Effects of ZD7288 on tremor induction in nontremulous TRMR rats. Duration and intensity of tremor observed in TRMR rats that received vehicle or ZD7288. Data are presented as the mean ± SEM of seven (vehicle) or eight (ZD7288) animals. *P<0.05, **P<0.01 vs. pre-treatment control levels (pre).
Mentions: To determine whether HCN1 channel dysfunction is responsible for the generation of tremors in vivo, we evaluated the actions of a selective HCN1 channel blocker, ZD7288, in nontremulous TRMR and WTC rats, which carry the tm deletion or not, respectively, on identical genetic backgrounds (Fig 4A). When ZD7288 (30 μg/rat) was microinjected into the LV, intensive body tremors were evoked in all TRMR rats, but in none of the WTC rats (Fig 4B). The clinical manifestation of the induced tremor was comparable with that of the TRM rats and significant increases in the duration and intensity of the tremor persisted during the 4 h observation period (intensity: P = 0.0014; duration: P = 0.0025). Vehicle alone did not induce tremors in the TRMR rats. This result clearly demonstrates that Hcn1 is the gene responsible for tremors (trm2) in our rat model of ET.

Bottom Line: We used a positional cloning approach and found a missense mutation (c. 1061 C>T, p.The A354V HCN1 failed to conduct hyperpolarization-activated currents in vitro, implicating it as a loss-of-function mutation.We propose that oligogenic, most probably digenic, inheritance is responsible for the genetic heterogeneity of ET.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, 569-1094, Japan.

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.

No MeSH data available.


Related in: MedlinePlus