A gene (ETM) for essential tremor maps to chromosome 2p22‐p25

Abstract

We report the results of linkage analysis in a large American family of Czech descent with dominantly inherited "pure" essential tremor (ET) and genetic anticipation. Genetic loci on chromosome 2p22-p25 establish linkage to this region with a maximum LOD score (Zmax) = 5.92 for the locus, D2S272. Obligate recombinant events place the ETM gene in a 15-cM candidate interval between the genetic loci D2S168 and D2S224. Repeat expansion detection analysis suggests that expanded CAG trinucleotide sequences are associated with ET. These findings will facilitate the search for an ETM gene and may further our understanding of the human motor system.

Genetic heterogeneity in autosomal dominant essential tremor

“…These loci were excluded in our family, suggesting yet another genetic locus we propose to call ETM3, for autosomal dominant ET. Phenotypically, the affected members of our family exhibited classic ET, and in this regard, our family did not differ clinically from the three families studied by Higgins et al 8,9 and the 16 families studied by Gulcher et al 7 Therefore, the genetic heterogeneity of ET is not reflected in the phenotypes of different families. Earlier age of onset was also noted by Higgins et al 9 ; however, this clinical anticipation may be related to ascertainment bias.…”

“…Higgins et al 8 reported linkage to 2p22-p25 in a large American family of Czech descent with ET and in three other American families. 9 Gulcher et al 7 reported linkage to 3q13 in 16 Icelandic families with 75 affected individuals.…”

“…A second locus, ETM2, on chromosome 2p22-p25, was subsequently identified by linkage analysis of a large family of Czech descent. 8 Later, Higgins et al 9 presented evidence for linkage of three unrelated American families with ET to the ETM2 locus. Recently, a chromosome 4p haplotype was reported for Lewy body parkinsonism (LBP) that also segregated among individuals in the pedigree who exhibited only postural tremor consistent with ET 10 (MIM 168601).…”

Dopamine receptor D3 gene and essential tremor in large series of German, Danish and French patients

“…3 -5 At least three chromosomal loci (ETM) have been identified by linkage analysis so far. ETM1 has been mapped in Icelandic families on chromosome 3q13, 6 ETM2 in North American families on chromosome 2p22 -p25 7 and ETM3 has been identified in North American families on chromosome 6p23. 8 The 10 cM interval of the ETM1 region contains approximately 70 genes according to different electronic sources (National Centre of Biological Investigation (NCBI); Ensembl genome browser), including the dopamine D 3 receptor (DRD3) gene in which three synonymous and one non-synonymous SNP have been reported.…”

A functional variant of the dopamine D 3 receptor is associated with risk and age-at-onset of essential tremor

“…There is a definite increase in prevalence of ET with age; prevalence has thus been reported as high as 22% in elderly populations (1). Previous genome-wide scans have identified two ET loci: a first study of 16 Icelandic families (6) found only one ET locus (ETM1, also called FET1) on chromosome 3q13; a second locus (ETM2) on chromosome 2p22-25 was subsequently identified in a large family of Czech descent (7). Although an A265G substitution in the HS1-binding protein 3 gene (HS1-BP3) was reported in ET families (8), a study of a larger series of affected families and controls found no evidence of cosegregation of the A265G polymorphism with ET (9).…”