Limits...
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

Immunohistochemical analysis of Fos expression induced by ZD7288 in TRMR rats.Effects of ZD7288 on regional Fos expression in TRMR rats. Inset: representative photographs of Fos-immunoreactive cells in the IO. Scale bar: 100 μm. Data are presented as the mean ± SEM of seven (vehicle) or eight (ZD7288) animals. *P<0.05 vs. control (vehicle).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4430019&req=5

pone.0123529.g005: Immunohistochemical analysis of Fos expression induced by ZD7288 in TRMR rats.Effects of ZD7288 on regional Fos expression in TRMR rats. Inset: representative photographs of Fos-immunoreactive cells in the IO. Scale bar: 100 μm. Data are presented as the mean ± SEM of seven (vehicle) or eight (ZD7288) animals. *P<0.05 vs. control (vehicle).

Mentions: To identify brain sites that were activated by ZD7288 in TRMR rats, we further analyzed regional Fos expression in ZD7288-treated TRMR rats. A marked and significant elevation in Fos expression was observed in the IO (P = 0.0495), compared with the TRMR rats given vehicle alone (Fig 5). These findings indicate that inhibition of HCN1 channels by ZD7288 causes excitation of IO neurons concomitantly with the generation of tremors.


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)

Immunohistochemical analysis of Fos expression induced by ZD7288 in TRMR rats.Effects of ZD7288 on regional Fos expression in TRMR rats. Inset: representative photographs of Fos-immunoreactive cells in the IO. Scale bar: 100 μm. Data are presented as the mean ± SEM of seven (vehicle) or eight (ZD7288) animals. *P<0.05 vs. control (vehicle).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4430019&req=5

pone.0123529.g005: Immunohistochemical analysis of Fos expression induced by ZD7288 in TRMR rats.Effects of ZD7288 on regional Fos expression in TRMR rats. Inset: representative photographs of Fos-immunoreactive cells in the IO. Scale bar: 100 μm. Data are presented as the mean ± SEM of seven (vehicle) or eight (ZD7288) animals. *P<0.05 vs. control (vehicle).
Mentions: To identify brain sites that were activated by ZD7288 in TRMR rats, we further analyzed regional Fos expression in ZD7288-treated TRMR rats. A marked and significant elevation in Fos expression was observed in the IO (P = 0.0495), compared with the TRMR rats given vehicle alone (Fig 5). These findings indicate that inhibition of HCN1 channels by ZD7288 causes excitation of IO neurons concomitantly with the generation of tremors.

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