Mitochondrial serine protease HTRA2 p.G399S in a 6-generation kindred with Essential Tremor and Parkinsons Disease. H. Unal Gulsuner1, S. Gulsuner2, N. Durmaz Mercan3, O. E. Onat4, T. Walsh2, H. Shahin5, O. Dogu6, T. Kansu7, H. Topaloglu8, B. Elibol7, C. Akbostanci3, M.-C. King2, T. Ozcelik4, A. B. Tekinay1 1) Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), Bilkent University, Ankara, Turkey; 2) Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA; 3) Department of Neurology, Faculty of Medicine, Ankara University, Ankara, Turkey; 4) Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey; 5) Department of Life Sciences, Bethlehem University, Bethlehem, Palestinian Territory; 6) Department of Neurology, Faculty of Medicine, Mersin University, Mersin, Turkey; 7) Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey; 8) Department of Pediatrics, Neurology Unit, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
Essential tremor (ET) is one of the most common movement disorders in humans. It is characterized primarily by postural and kinetic tremor of the arms and hands, but the head, legs, voice, and other regions of the body may also be affected. Genes responsible for most of ET are not yet known, with mutation of FUS identified as responsible for the phenotype in one family. Our study focused on a 6-generation family of Turkish ancestry including 16 relatives with varying degrees of tremor. Three of these relatives developed ET as children and signs of Parkinsons disease (PD) in middle age. We carried out whole exome sequencing using DNA from three severely affected relatives, and then genotyped all shared putatively damaging variants in 24 informative family members. Both dominant and recessive modes of inheritance were considered. Exactly one potentially damaging variant, HTRA2 p.G399S, co-segregated with ET in the family. Of 16 affected individuals, 5 were homozygous and 11 were heterozygous for the variant allele 399Ser. The 5 homozygous individuals included the 3 relatives with both ET and PD and 2 relatives younger than age 30 who developed ET at ages 10 and 12 years. HTRA2 genotype was significantly associated with age at onset of tremor (mean onset for homozygotes age 19 and for heterozygotes age 40, P = 0.010), severity of postural tremor (P = 0.0002) and severity of kinetic tremor (P = 0.011). No mutations in the complete HTRA2 sequence were detected in probands of 25 other Turkish families with ET. Among Turkish controls (ages 20-30), 2 of 364 were heterozygous for HTRA2 p.G399S (allele frequency 0.0027). HtrA2 deficiency is responsible for motor neuron degeneration in the mouse model Mnd2. Heterozygosity for HTRA2 p.G399S was associated with PD in some, but not all, studies. Our results suggest that HTRA2 p.G399S is responsible for hereditary ET in this kindred and that homozygosity for this variant leads to development of parkinsonian features. Although ET and PD have been known as distinct entities, our results show the co-existence of both disorders. These results might reveal shared etiologic factors underlying ET and PD phenotypes.
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