| Author |
Akbostanci, Cenk Walsh, Tom Dogu, Okan Ozcelik, Tayfun King, Mary-claire Lee, Ming K. Shahin, Hashem Gulsuner, Suleyman Elibol, Bulent Onat, Onur Emre Unal Gulsuner, Hilal Mercan, Fatma Nazli Kansu, Tulay Tekinay, Ayse B. Topaloglu, Haluk |
| Description |
Author Affiliation: Unal Gulsuner H ( Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), and Departments of Medicine and of Genome Sciences, University of Washington, Seattle, WA 98195); Gulsuner S ( Departments of Medicine and of Genome Sciences, University of Washington, Seattle, WA 98195); Mercan FN ( Department of Neurology, Faculty of Medicine, Ankara University, Ankara 06100, Turkey); Onat OE ( Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey); Walsh T ( Departments of Medicine and of Genome Sciences, University of Washington, Seattle, WA 98195); Shahin H ( Department of Life Sciences, Bethlehem University, Bethlehem 92248, Palestinian Authority); Lee MK ( Departments of Medicine and of Genome Sciences, University of Washington, Seattle, WA 98195); Dogu O ( Department of Neurology, Faculty of Medicine, Mersin University, Mersin 33343, Turkey); Kansu T ( Department of Neurology and.); Topaloglu H ( Department of Pediatrics, Neurology Unit, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.); Elibol B ( Department of Neurology and.); Akbostanci C ( Department of Neurology, Faculty of Medicine, Ankara University, Ankara 06100, Turkey); King MC ( Departments of Medicine and of Genome Sciences, University of Washington, Seattle, WA 98195); Ozcelik T ( Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), and Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey); Tekinay AB ( Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), and mcking@u.washington.edu tozcelik@fen.bilkent.edu.tr atekinay@unam.bilkent.edu.tr.); |
| Abstract |
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. |
