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Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole-exome sequencing and targeted resequencing in three ET families.  In vitro  and  in vivo  experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole-exome sequencing revealed a missense mutation in  TENM4  segregating in an autosomal-dominant fashion in an ET family. Subsequent targeted resequencing of  TENM4  led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic  TENM4  alleles across the three families. Consistent with a dominant mode of inheritance,  in vitro  analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a  Tenm4  knockout mouse displaying an ET phenotype, implicates  TENM4  in ET. Together with previous studies of  TENM4  in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorder.

Missense mutations in TENM4 , a regulator of axon guidance and central myelination, cause essential tremor