A5072547508- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- ATP Synthase and ATPases Research
- RNA modifications and cancer
- Genomics and Rare Diseases
- Genetics and Neurodevelopmental Disorders
- Cancer, Hypoxia, and Metabolism
- Biochemical Acid Research Studies
- Biochemical and Molecular Research
- Ubiquitin and proteasome pathways
- Amino Acid Enzymes and Metabolism
- Diet and metabolism studies
- Manufacturing Process and Optimization
- RNA and protein synthesis mechanisms
- Neurogenetic and Muscular Disorders Research
- Congenital heart defects research
- Endoplasmic Reticulum Stress and Disease
- Neurological diseases and metabolism
- Alcoholism and Thiamine Deficiency
- Glioma Diagnosis and Treatment
- Metalloenzymes and iron-sulfur proteins
- Robotic Locomotion and Control
- Prosthetics and Rehabilitation Robotics
- Glycogen Storage Diseases and Myoclonus
- Neuroblastoma Research and Treatments
Salzburger Landeskliniken
2016-2025
Paracelsus Medical University
2016-2025
Medical University of Vienna
2025
Université Paris Cité
2024
University Children's Hospital Zurich
2024
Zentrum für Kinderheilkunde
2004-2023
Chiba Hospital
2023
University of Salzburg
2007-2022
Paracelsus Medizinische Privatuniversität
2006-2021
University Hospital Centre Zagreb
2021
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...
Mutations in the gene coding for catalytic subunit of mitochondrial DNA (mtDNA) polymerase gamma (POLG1) have recently been described patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype their families. POLG1 was sequenced from different European diagnostic research centres to define phenotypic spectrum advance understanding recurrence risks. were identified 38 cases, majority being sporadic compound heterozygotes. Eighty-nine sequence...
Abstract Epitranscriptome modifications are required for structure and function of RNA defects in these pathways have been associated with human disease. Here we identify the target previously uncharacterized 5-methylcytosine (m 5 C) methyltransferase NSun3 link m C energy metabolism. Using whole-exome sequencing, identified loss-of-function mutations NSUN3 a patient presenting combined mitochondrial respiratory chain complex deficiency. Patient-derived fibroblasts exhibit severe translation...
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...
Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was first to be genetically defined by a point mutation in DNA (mtDNA). A molecular diagnosis achieved up 95% of cases, vast majority which are accounted for 3 mutations within complex I subunit–encoding genes mtDNA (mtLHON). Here, we resolve enigma LHON absence pathogenic mutations. We describe biallelic nuclear encoded gene, DNAJC30, 33 unsolved patients from 29 families establish an autosomal...
<h3>Background</h3> Next generation sequencing has become the core technology for gene discovery in rare inherited disorders. However, interpretation of numerous sequence variants identified remains challenging. We assessed application exome diagnostics complex I deficiency, a disease with vast genetic heterogeneity. <h3>Methods</h3> Ten unrelated individuals deficiency were selected and sequential bioinformatic filtering. Cellular rescue experiments performed to verify pathogenicity novel...
Introduction Neuroblastoma is a malignant pediatric cancer derived from neural crest cells. It characterized by generalized reduction of mitochondrial oxidative phosphorylation. The goal the present study was to investigate effects calorie restriction and ketogenic diet on neuroblastoma tumor growth monitor potential adaptive mechanisms cancer's phosphorylation system. Methods Xenografts were established in CD-1 nude mice subcutaneous injection two cell lines having distinct genetic...
Whole-exome sequencing and autozygosity mapping studies, independently performed in subjects with defective combined mitochondrial OXPHOS-enzyme deficiencies, identified a total of nine disease-segregating FBXL4 mutations seven unrelated disease families, composed six singletons three siblings. All manifested early-onset lactic acidemia, hypotonia, developmental delay caused by severe encephalomyopathy consistently associated progressive cerebral atrophy variable involvement the white...
Abstract Purpose: Many solid tumors exhibit abnormal aerobic metabolism characterized by increased glycolytic capacity and decreased cellular respiration. Recently, mutations in the nuclear encoded mitochondrial enzymes fumarate hydratase succinate dehydrogenase have been identified certain tumor types, thus demonstrating a direct link between energy tumorigenesis. Although genome (mitochondrial DNA, mtDNA) also can affect mtDNA alterations are frequently observed cells, evidence linking...
To determine the epidemiology of biliary atresia (BA) in Switzerland, outcome children from diagnosis, and prognostic factors.The records all patients with BA born Switzerland between January 1994 December 2004 were analyzed. Survival rates calculated Kaplan-Meier method, factors evaluated log rank test. Median follow up was 58 months (range, 5-124).BA diagnosed 48 children. Incidence 1 17,800 live births (95% confidence interval 1/13,900-1/24,800), without significant regional, annual, or...
Respiratory chain deficiencies exhibit a wide variety of clinical phenotypes resulting from defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mtDNA or nuclear genes coding for proteins. The underlying pathomechanisms affect numerous pathways involved physiology. By whole-exome and candidate gene sequencing, we identified 11 individuals 9 families carrying compound heterozygous homozygous GTPBP3, encoding...
The human mitochondrial genome encodes RNA components of its own translational machinery to produce the 13 mitochondrial-encoded subunits respiratory chain. Nuclear-encoded gene products are essential for all processes within organelle, including processing. Transcription generates large polycistronic transcripts punctuated by 22 (mt) tRNAs that conventionally cleaved RNase P-complex and Z activity ELAC2 at 5' 3' ends, respectively. We report identification mutations in five individuals with...
Multiple acyl-CoA dehydrogenase deficiencies (MADDs) are a heterogeneous group of metabolic disorders with combined respiratory-chain deficiency and neuromuscular phenotype. Despite recent advances in understanding the genetic basis MADD, number cases remain unexplained. Here, we report clinically relevant variants FLAD1, which encodes FAD synthase (FADS), as cause MADD dysfunction nine individuals recruited from centers six countries. In most individuals, identified biallelic frameshift...
F1Fo-ATP synthase is a key enzyme of mitochondrial energy provision producing most cellular ATP. So far, diseases caused by isolated disorders the ATP have been shown to result from mutations in mtDNA genes for subunits ATP6 and ATP8 or nuclear encoding biogenesis factors TMEM70 ATPAF2. Here, we describe patient with homozygous p.Tyr12Cys mutation ε subunit encoded gene ATP5E. The 22-year-old woman presented neonatal onset, lactic acidosis, 3-methylglutaconic aciduria, mild mental...
Neuroblastoma (NB) is a pediatric malignancy characterized by marked reduction in aerobic energy metabolism. Recent preclinical data indicate that targeting this metabolic phenotype ketogenic diet (KD), especially combination with calorie restriction, slows tumor growth and enhances metronomic cyclophosphamide (CP) therapy of NB xenografts. Because restriction would be contraindicated most cancer patients, the aim present study was to optimize KD such tumors are sensitized CP without need...
<h3>Background</h3> Mitochondria are dynamic organelles which undergo continuous fission and fusion to maintain their diverse cellular functions. Components of the machinery partly shared between mitochondria peroxisomes, inherited defects in two such components (dynamin-related protein (DRP1) ganglioside-induced differentiation-associated 1 (GDAP1)) have been associated with human disease. Deficiency a third component (mitochondrial factor, MFF) was recently reported one index patient,...
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...