RGD Reference Report - Hcn1 is a tremorgenic genetic component in a rat model of essential tremor. - Rat Genome Database

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

Authors: Ohno, Y  Shimizu, S  Tatara, A  Imaoku, T  Ishii, T  Sasa, M  Serikawa, T  Kuramoto, T 
Citation: Ohno Y, etal., PLoS One. 2015 May 13;10(5):e0123529. doi: 10.1371/journal.pone.0123529. eCollection 2015.
RGD ID: 11060746
Pubmed: (View Article at PubMed) PMID:25970616
DOI: Full-text: DOI:10.1371/journal.pone.0123529

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.


Disease Annotations    
Tremor  (IAGP,IMP,ISO)

Phenotype Annotations    

Mammalian Phenotype
tremors  (IAGP)
Objects Annotated

Genes (Rattus norvegicus)
Hcn1  (hyperpolarization-activated cyclic nucleotide-gated potassium channel 1)
Hcn1A354V  (hyperpolarization-activated cyclic nucleotide-gated potassium channel 1; A354V mutant)

Genes (Mus musculus)
Hcn1  (hyperpolarization activated cyclic nucleotide gated potassium channel 1)

Genes (Homo sapiens)
HCN1  (hyperpolarization activated cyclic nucleotide gated potassium channel 1)

TRM/Kyo  (tremor rat)
TRMR/Kyo  (tremor resistant)
WTC/Kyo  (NA)

Additional Information