Genetic mouse models of essential tremor: are they essential?

Abstract

The causative genes for essential tremor (ET), one of the most common genetic neurological disorders, have eluded scientists despite intensive search. Two gene loci linked to ET, one on chromosome 3q13 and another on chromosome 2p24.1, have been identified, and a missense mutation in the HS1-BP3 gene on the 2p has been suggested as the cause of the disorder in about 10% of American ET patients. Therefore, the genetic basis for the vast majority of familial ET is still unknown. In this issue of the JCI, the gene coding for the γ-aminobutyric acid A (GABA A ) receptor α1 subunit is suggested as a potential candidate gene for ET, as mice lacking the gene express a phenotype that overlaps with some clinical characteristics of the human condition (see the related article beginning on page 774).

Alcohol in essential tremor and other movement disorders

“…As Et‐OH interferes with GABAergic transmission, the GABA system has been studied in some experimental models. The kinetic, alcohol‐responsive tremor exhibited by GABA A receptor α1 −/− mice has been proposed as model for ET, as the loss of GABA A receptors has been shown to impair signaling by cerebellar Purkinje cells and the mice express otherwise classic, alcohol‐responsive tremor 84, 85. However, GABA A receptor α1 gene ( GABRA1 ) mutation does not appear to be a major genetic cause of ET in Caucasian subjects 86…”

Hepatitis B virus viral load and treatment decision

“…The first is that genetic abnormalities combined with putative nongenetic (e.g., environmental) factors lead to neurodegeneration that causes tremor and other disturbances of neurologic function 64. The second hypothesis is that genetic abnormalities or possibly nongenetic factors cause a dynamic oscillatory disturbance of the motor system 105, 106. In this alternative hypothesis, ET is not a primary neurodegenerative disease, rather it is a dynamic oscillatory disturbance that is theoretically reversible, but if allowed to continue, the abnormal neuronal discharge may cause secondary neuronal damage and neuroplastic change.…”

Heritable essential tremor‐idiopathic normal pressure hydrocephalus (ETINPH)

“…However, no gene has yet been identified for ET. Furthermore, no animal model has yet been generated that exactly recreates all features of any of the known tremor disorders in humans [Wilms et al, 1999;Jankovic and Noebels, 2005]. In a series of efforts to try to identify ETM2 gene, a missense mutation (C/G) causing a glycine for an alanine substitution (A265G variant) in the HS1 binding protein-3 gene (HS1BP3) was identified in the minimal critical region (MCR) at the ETM2 locus and was defined to be associated with ET among two ET families linked to this locus [Higgins et al, 2005].…”