Felix Distelmaier
A5009594548- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- ATP Synthase and ATPases Research
- Genomics and Rare Diseases
- RNA modifications and cancer
- Genetics and Neurodevelopmental Disorders
- Coenzyme Q10 studies and effects
- Biochemical and Molecular Research
- Cerebral Venous Sinus Thrombosis
- Biochemical Acid Research Studies
- Neonatal Health and Biochemistry
- Diet and metabolism studies
- Neurosurgical Procedures and Complications
- Genetics, Aging, and Longevity in Model Organisms
- RNA Research and Splicing
- Advanced battery technologies research
- DNA Repair Mechanisms
- Blood disorders and treatments
- RNA regulation and disease
- Cellular transport and secretion
- Epilepsy research and treatment
- Alcoholism and Thiamine Deficiency
- RNA and protein synthesis mechanisms
- Genetic Neurodegenerative Diseases
- Metalloenzymes and iron-sulfur proteins
Heinrich Heine University Düsseldorf
2015-2024
Düsseldorf University Hospital
2015-2024
German Center for Pediatric and Adolescent Rheumatology
2024
Innsbruck Medical University
2023
Universität Innsbruck
2023
Radboud University Nijmegen
2007-2022
Radboud University Medical Center
2007-2022
Radboud Institute for Molecular Life Sciences
2022
Children's Clinical University Hospital
2013-2020
Ludwig-Maximilians-Universität München
2020
Abstract Across a variety of Mendelian disorders, ∼50–75% patients do not receive genetic diagnosis by exome sequencing indicating disease-causing variants in non-coding regions. Although genome principle reveals all variants, their sizeable number and poorer annotation make prioritization challenging. Here, we demonstrate the power transcriptome to molecularly diagnose 10% (5 48) mitochondriopathy identify candidate genes for remainder. We find median one aberrantly expressed gene, five...
Abstract Background Lack of functional evidence hampers variant interpretation, leaving a large proportion individuals with suspected Mendelian disorder without genetic diagnosis after whole genome or exome sequencing (WES). Research studies advocate to further sequence transcriptomes directly and systematically probe gene expression defects. However, collection additional biopsies establishment lab workflows, analytical pipelines, defined concepts in clinical interpretation aberrant are...
Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency. Few conditions are known to cause recurrent acute (RALF), about 50% of cases, the underlying molecular remains unresolved. Exome sequencing five unrelated individuals with fever-dependent RALF revealed biallelic mutations NBAS. Subsequent Sanger NBAS 15 additional or ALF identified compound heterozygous an six from families. Immunoblot analysis mutant fibroblasts showed reduced protein levels its proposed...
Unexplained global developmental delay and epilepsy in childhood pose a major socioeconomic burden. Progress defining the molecular bases does not often translate into effective treatment. Notable exceptions include certain inborn errors of metabolism amenable to dietary intervention. CAD encodes multifunctional enzyme involved de novo pyrimidine biosynthesis. Alternatively, pyrimidines can be recycled from uridine. Exome sequencing three families identified biallelic mutations four children...
Abstract Thioredoxin 2 (TXN2; also known as Trx2) is a small mitochondrial redox protein essential for the control of reactive oxygen species homeostasis, apoptosis regulation and cell viability. Exome sequencing in 16-year-old adolescent suffering from an infantile-onset neurodegenerative disorder with severe cerebellar atrophy, epilepsy, dystonia, optic peripheral neuropathy, uncovered homozygous stop mutation TXN2. Analysis patient-derived fibroblasts demonstrated absence TXN2 protein,...
To delineate the phenotypic and genotypic spectrum in carriers of mitochondrial MT-ATP6 mutations a large international cohort.We analyzed detail clinical, genetical, neuroimaging data from 132 mutation national registries local databases Europe, USA, Japan, China.We identified 113 clinically affected 19 asymptomatic individuals with known pathogenic mutation. The most frequent were m.8993 T > G (53/132, 40%), C (30/132, 23%), m.9176 m.9185 (12/132, 9%). degree heteroplasmy was high both...
Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and motor abnormalities have a documented underlying monogenic defect, primarily due de novo variants. Still, the overall burden variants well novel disease genes in NDDs await discovery. We performed parent-offspring trio exome sequencing 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The diagnostic yield was 49.8% (n =...
Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it also has several other functions in cellular metabolism. One them to function as an electron carrier reaction catalyzed by sulfide:quinone oxidoreductase (SQR), which catalyzes first hydrogen sulfide oxidation pathway. Therefore, SQR may be affected CoQ deficiency. Using human skin fibroblasts and two mouse models with primary deficiency, we demonstrate that severe deficiency causes reduction levels activity,...
COA6/C1ORF31 is involved in cytochrome c oxidase (complex IV) biogenesis. We present a new pathogenic COA6 variant detected patient with neonatal hypertrophic cardiomyopathy and isolated complex IV deficiency. For the first time, clinical details about COA6-deficient are given fibroblasts functionally characterized: protein undetectable steady-state levels of several its subunits reduced. The monomeric COX1 assembly intermediate accumulates. Using pulse-chase experiments, we demonstrate an...
To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum COQ8A-ataxia in a large worldwide cohort, provide first progression data, including treatment response to Q10 (CoQ10).Cross-modal analysis multicenter cohort 59 COQ8A patients, genotype-phenotype correlations, 3D-protein modeling, vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, CoQ10 data.Fifty-nine patients (39 novel) with 44...
Mitochondrial membrane potential (Deltapsi) is key to mitochondrial function and cellular survival. Here, we aimed develop an automated protocol allowing sensitive quantification of Deltapsi in living cells at the level individual mitochondria. Human skin fibroblasts were stained with fluorescent cation tetramethyl rhodamine methyl ester (TMRM), which sequestered by mitochondria according their Deltapsi. Cells visualized videomicroscopy acquired images processed generate a...
Malfunction of mitochondrial complex I caused by nuclear gene mutations causes early-onset neurodegenerative diseases. Previous work using cultured fibroblasts complex-I-deficient patients revealed elevated levels reactive oxygen species (ROS) and reductions in both total Ca(2+) content the endoplasmic reticulum (ER(Ca)) bradykinin(Bk)-induced increases cytosolic free ([Ca(2+)](C); [Ca(2+)](M)) ATP ([ATP](C); [ATP](M)) concentration. Here, we determined membrane potential (Delta psi) patient...
Aims: Cell regulation by signaling reactive oxygen species (sROS) is often incorrectly studied through extracellular oxidant addition. Here, we used the membrane-permeable antioxidant Trolox to examine role of sROS in mitochondrial morphology, oxidative phosphorylation (OXPHOS), and cytosolic calcium (Ca2+) handling healthy human skin fibroblasts. Results Innovation: treatment reduced levels 5-(and-6)-chloromethyl-2′,7′-dichlorodihydro-fluorescein (CM-H2DCF) oxidizing ROS, lowered cellular...