title: Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease.
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.
authors.affiliation: 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;
authors.forename: Hilal
authors.initials: H
authors.lastname: Unal Gulsuner
authors.affiliation: Departments of Medicine and of Genome Sciences, University of Washington, Seattle, WA 98195;
authors.forename: Suleyman
authors.initials: S
authors.lastname: Gulsuner
authors.affiliation: Department of Neurology, Faculty of Medicine, Ankara University, Ankara 06100, Turkey;
authors.forename: Fatma Nazli
authors.initials: FN
authors.lastname: Mercan
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey;
authors.forename: Onur Emre
authors.initials: OE
authors.lastname: Onat
authors.affiliation: Departments of Medicine and of Genome Sciences, University of Washington, Seattle, WA 98195;
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.affiliation: Department of Life Sciences, Bethlehem University, Bethlehem 92248, Palestinian Authority;
authors.forename: Hashem
authors.initials: H
authors.lastname: Shahin
authors.affiliation: Departments of Medicine and of Genome Sciences, University of Washington, Seattle, WA 98195;
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Department of Neurology, Faculty of Medicine, Mersin University, Mersin 33343, Turkey; and.
authors.forename: Okan
authors.initials: O
authors.lastname: Dogu
authors.affiliation: Department of Neurology and.
authors.forename: Tulay
authors.initials: T
authors.lastname: Kansu
authors.affiliation: Department of Pediatrics, Neurology Unit, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.
authors.forename: Haluk
authors.initials: H
authors.lastname: Topaloglu
authors.affiliation: Department of Neurology and.
authors.forename: Bulent
authors.initials: B
authors.lastname: Elibol
authors.affiliation: Department of Neurology, Faculty of Medicine, Ankara University, Ankara 06100, Turkey;
authors.forename: Cenk
authors.initials: C
authors.lastname: Akbostanci
authors.affiliation: Departments of Medicine and of Genome Sciences, University of Washington, Seattle, WA 98195; mcking@u.washington.edu tozcelik@fen.bilkent.edu.tr atekinay@unam.bilkent.edu.tr.
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.affiliation: Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), and Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey; mcking@u.washington.edu tozcelik@fen.bilkent.edu.tr atekinay@unam.bilkent.edu.tr.
authors.forename: Tayfun
authors.initials: T
authors.lastname: Ozcelik
authors.affiliation: 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.
authors.forename: Ayse B
authors.initials: AB
authors.lastname: Tekinay
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D020329:Essential Tremor / Q000235:genetics*; D005260:Female; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D012697:Serine Endopeptidases / Q000235:genetics*; D055815:Young Adult
chemical_list: D024101:Mitochondrial Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse
keywords: DNA sequencing; gene identification; mitochondrial dysfunction; mutation; neurodegenerative disease