ArticleJournal of inherited metabolic disease2017
Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome associated with 3-methylglutaconic aciduria.
Article in Journal of inherited metabolic disease, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 29 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
- Hypoxia rescues complex 1-associated disease caused by proteostatic defects.Nature metabolism · 2026Article
- Oxygen relief for a proteostasis-driven disease associated with mitochondrial complex I dysfunction.Nature metabolism · 2026Article
- Article
- HtrA2/Omi: potential therapeutic targets for neurodegenerative diseases.Frontiers in pharmacology · 2026Review
- Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.Biochemical Society transactions · 2025Article
- YME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria.Journal of inherited metabolic disease · 2025Article
- CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.Journal of inherited metabolic disease · 2025Review
- Disorders of organic acid metabolism and epilepsy.Acta epileptologica · 2024Review
- CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex.The Journal of cell biology · 2024Article
- Biallelic variants in HTRA2 cause 3-methylglutaconic aciduria mitochondrial disorder: case report and literature review.Frontiers in genetics · 2023Article
- Mitochondrial Protein Homeostasis and Cardiomyopathy.International journal of molecular sciences · 2022Review
- Inborn errors of metabolism associated with 3-methylglutaconic aciduria.Clinica chimica acta; international journal of clinical chemistry · 2021Review
- Identification of a novel heterozygous guanosine monophosphate reductase (GMPR) variant in a patient with a late-onset disorder of mitochondrial DNA maintenance.Clinical genetics · 2020Article
- Mitochondrial diseases: expanding the diagnosis in the era of genetic testing.Journal of translational genetics and genomics · 2020Article
- Parkinson Disease from Mendelian Forms to Genetic Susceptibility: New Molecular Insights into the Neurodegeneration Process.Cellular and molecular neurobiology · 2018Review
- Clinical, biochemical, and genetic features of four patients with short-chain enoyl-CoA hydratase (ECHS1) deficiency.American journal of medical genetics. Part A · 2018Article
- NGS Technologies as a Turning Point in Rare Disease Research , Diagnosis and Treatment.Current medicinal chemistry · 2018Review
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Authors and funding
18 authors at 9 institutions in 2 countries.
Funding
Abstract
Mitochondrial diseases collectively represent one of the most heterogeneous group of metabolic disorders. Symptoms can manifest at any age, presenting with isolated or multiple-organ involvement. Advances in next-generation sequencing strategies have greatly enhanced the diagnosis of patients with mitochondrial disease, particularly where a mitochondrial aetiology is strongly suspected yet OXPHOS activities in biopsied tissue samples appear normal. We used whole exome sequencing (WES) to identify the molecular basis of an early-onset mitochondrial syndrome-pathogenic biallelic variants in the HTRA2 gene, encoding a mitochondria-localised serine protease-in five subjects from two unrelated families characterised by seizures, neutropenia, hypotonia and cardio-respiratory problems. A unifying feature in all affected children was 3-methylglutaconic aciduria (3-MGA-uria), a common biochemical marker observed in some patients with mitochondrial dysfunction. Although functional studies of HTRA2 subjects' fibroblasts and skeletal muscle homogenates showed severely decreased levels of mutant HTRA2 protein, the structural subunits and complexes of the mitochondrial respiratory chain appeared normal. We did detect a profound defect in OPA1 processing in HTRA2-deficient fibroblasts, suggesting a role for HTRA2 in the regulation of mitochondrial dynamics and OPA1 proteolysis. In addition, investigated subject fibroblasts were more susceptible to apoptotic insults. Our data support recent studies that described important functions for HTRA2 in programmed cell death and confirm that patients with genetically-unresolved 3-MGA-uria should be screened by WES with pathogenic variants in the HTRA2 gene prioritised for further analysis.
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