Aysel Sabuncu Brain Research Center (BAM)

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Browsing Aysel Sabuncu Brain Research Center (BAM) by Author "Akbostanci, C."

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    Mitochondrial serine protease HTRA2 p.G3999S in a kindred with essential tremor and Parkinson disease
    (National Academy of Sciences, 2014) Gülümser, Hilal Ünal; Gulsuner, S.; Mercan, F. N.; Onat, Onur Emre; Walsh, T.; Shahin, H.; Lee, M. K.; Dogu, O.; Kansu, T.; Topaloglu, H.; Elibol, B.; Akbostanci, C.; King, M. C.; Özçelik, Tayfun; Tekinay, Ayşe B.
    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.
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    Reply to tzoulis et al.: genetic and clinical heterogeneity of essential tremor
    (National Academy of Sciences, 2015) Gülsuner, Hilal Ünal; Gülsuner, S.; Mercan, F.; Onat, Onur Emre; Walsh, T.; Shahin, H.; Lee, M.; Dogu, O.; Kansu, T.; Topaloglu, H.; Elibol, B.; Akbostanci, C.; King, M. -C.; Özçelik, Tayfun; Tekinay, Ayse B.
    In addressing our recent report of HTRA2 p.G399S as the gene and mutation responsible for essential tremor and subsequent Parkinson disease in a large kindred (1), Tzoulis et al. (2) screened this mutation in patients with Parkinson disease, essential tremor, tremulous cervical dystonia, and nontremulous cervical dystonia patients, and did not find a significant difference in carrier frequency compared with the general population. Their observation replicates our experience, in that in the kindred of our study, HTRA2 p.G399S was responsible for essential tremor and, among homozygotes, for Parkinson disease, but as we reported, this allele was not responsible for essential tremor in other families from the same population. Both these observations support the conclusion that essential tremor is a heterogeneous disease, both clinically and genetically (3). In addition to HTRA2, two other genes for essential tremor have been identified: DNAJC13 and FUS, and still other responsible genes have been mapped to chromosomes 2p22-24, 3q13, and 6p23 (1, 4). In any one patient, mutation at only one of these genes is sufficient for development of essential tremor, but the responsible gene differs among patients. These two features—the severity of individual causal mutations and different responsible genes in different families—are characteristic of genetic heterogeneity of complex diseases generally (5). Phenotypic features of a genetically heterogeneous disease may offer clues as to the responsible gene. In the family harboring mutation in HTRA2, Parkinson disease appeared after more than a decade of essential tremor. Also, cervical dystonia was not among the presenting signs in any of the family members. These clinical features differ from the series of patients screened by Tzoulis et al. Some of the patients screened by Tzoulis et al. may harbor HTRA2 mutations other than p.G399S that would be revealed by more complete sequencing; this would be interesting to learn. It is also possible that mutations in the other known genes for essential tremor may be present in these patients. If not, then these patients, like those from the other kindreds in our series, offer the opportunity to identify additional causal genes for essential tremor.