ArticleProceedings of the National Academy of Sciences of the United States of America2014
Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed, 132 citations in OpenAlex.
- Novel Clinical and Neurophysiological Insights in Neonatal-Onset 3-Methylglutaconic Aciduria Type VIII due to HTRA2 Mutations.Molecular genetics & genomic medicine · 2026Article
- Reduced Mitochondrial DNA Copy Number and Telomere Length in Essential Tremor Patients: Evidence from an Age- and Sex-Adjusted Cross-Sectional Case-Control Study.International journal of molecular sciences · 2026Article
- A central role for PINK1 in governing local mitochondrial biogenesis and degradation in neurons.Cellular and molecular life sciences : CMLS · 2026Review
- HtrA2/Omi: potential therapeutic targets for neurodegenerative diseases.Frontiers in pharmacology · 2026Review
- Tremor pathophysiology.Clinical parkinsonism & related disorders · 2026Review
- Therapeutic potential of melatonin-induced mitophagy in the pathogenesis of Alzheimer's disease.Inflammopharmacology · 2025Review
- Clinical and Genetic Characteristics of Patients with Essential Tremor Who Develop Parkinson's Disease.Medicina (Kaunas, Lithuania) · 2025Article
- A heterozygous variation of PINK1 is potentially associated with essential tremor in a Chinese family.Neurogenetics · 2025Article
- Identification and validation of autophagy-related genes in sepsis based on bioinformatics studies.Virology journal · 2025Article
- Article
- Structural basis of substrate recognition and allosteric activation of the proapoptotic mitochondrial HtrA2 protease.Nature communications · 2024Article
- Intraneuronal β-amyloid impaired mitochondrial proteostasis through the impact on LONP1.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Gene Expression Analysis of Laser-Captured Purkinje Cells in the Essential Tremor Cerebellum.Cerebellum (London, England) · 2023Article
- A NovelGenes · 2023Article
- Biallelic variants in HTRA2 cause 3-methylglutaconic aciduria mitochondrial disorder: case report and literature review.Frontiers in genetics · 2023Article
- Structural basis of protein substrate processing by human mitochondrial high-temperature requirement A2 protease.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Biological mechanisms of aging predict age-related disease co-occurrence in patients.Aging cell · 2022Article
- The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations.Frontiers in molecular neuroscience · 2022Review
- Probing allosteric interactions in homo-oligomeric molecular machines using solution NMR spectroscopy.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Essential tremor.Nature reviews. Disease primers · 2021Review
14 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 8 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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