Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability.


Hilal Unal Gulsunera,b, Suleyman Gulsunerb, Fatma Nazli Mercanc, Onur Emre Onatd, Tom Walshb, Hashem Shahine, Ming K. Leeb, Okan Doguf, Tulay Kansug, Haluk Topalogluh, Bulent Elibolg, Cenk Akbostancic, Mary-Claire Kingb,1, Tayfun Ozcelika,d,1, and Ayse B. Tekinaya,1




Essential tremor is one of the most frequent movement disorders of humans, but its causes remain largely unknown. In a six-generation family with both essential tremor and Parkinson disease, we identified a rare missense mutation of HTRA2 as the causative allele. Family members homozygous for this allele were more severely affected than those heterozygous for this allele. The same mutation had been associated with Parkinson characteristics in mouse mutants and with Parkinson disease in some, but not all, epidemiologic studies. Our results suggest that HTRA2 may be responsible for essential tremor in some families and that homozygosity for damaging alleles of HTRA2 may be responsible for Parkinson disease.




Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p.G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.



PNAS December 24 2014; vol.111, no.51: 18285–18290


Fig. 4. Schematic representation of the HTRA2 protein and its activation against mitochondrial stress. (A) Locations of all reported mutations in HTRA2 in persons with essential tremor or Parkinson disease. The full-length HTRA2 protein consists of a transmembrane domain (TM; residues 105–124), a conserved catalytic trypsin-like serine protease domain (Tryp_SPc; residues 178–342), and a C-terminal PDZ domain (residues 363–445). Phosphorylation sites are at Ser142 and Ser400. (B) Oxidative stress results in the activation of p38 stress kinase pathway. In HTRA2, p38 phosphorylates serine at residue 142 in a PINK1-dependent manner; CDK5 phosphorylates serine at residue 400, increasing the proteolytic activity of HTRA2. Active HTRA2 induces stress-responsive caspases. PINK1 also recruits Parkin, an E3 ubiquitin protein ligase, from cytosol to mitochondria to induce mitophagy. Red diamonds represent phosphorylation sites at residues 142 and 400. P, phosphorylation. Adapted by permission from Macmillan Publishers Ltd: Nature Cell Biology (20), copyright (2007).