A5070209892- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- ATP Synthase and ATPases Research
- Genetic Neurodegenerative Diseases
- RNA modifications and cancer
- RNA regulation and disease
- Genomics and Rare Diseases
- Parkinson's Disease Mechanisms and Treatments
- Metalloenzymes and iron-sulfur proteins
- Genetics and Neurodevelopmental Disorders
- Neurological diseases and metabolism
- RNA and protein synthesis mechanisms
- Genomics and Phylogenetic Studies
- Metabolomics and Mass Spectrometry Studies
- interferon and immune responses
- Nuclear Receptors and Signaling
- Ubiquitin and proteasome pathways
- Neurological disorders and treatments
- Protein Tyrosine Phosphatases
- Cardiomyopathy and Myosin Studies
- Neurogenetic and Muscular Disorders Research
- Muscle Physiology and Disorders
- Lysosomal Storage Disorders Research
- Genetic factors in colorectal cancer
- Hereditary Neurological Disorders
Fondazione IRCCS Istituto Neurologico Carlo Besta
2016-2025
University of Milan
2017-2025
Istituti di Ricovero e Cura a Carattere Scientifico
2012-2024
Weatherford College
2023
Paracelsus Medical University
2021
Baylor Scott & White Health
2017
Medical Research Council
2017
The University of Texas Southwestern Medical Center
2017
George Washington University
2017
MRC Mitochondrial Biology Unit
2017
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...
<h3>Objectives:</h3> The study was focused on leukoencephalopathies of unknown cause in order to define a novel, homogeneous phenotype suggestive common genetic defect, based clinical and MRI findings, identify the causal defect shared by patients with this phenotype. <h3>Methods:</h3> Independent next-generation exome-sequencing studies were performed 2 unrelated leukoencephalopathy. findings these compared available MRIs database unclassified leukoencephalopathies; 11 similar abnormalities...
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...
In the large group of genetically undetermined infantile-onset mitochondrial encephalopathies, multiple defects DNA-related respiratory-chain complexes constitute a frequent biochemical signature. order to identify responsible genes, we used exome-next-generation sequencing in selected cohort patients with this an isolated patient, found two mutant alleles for EARS2, gene encoding glutamyl–tRNA synthetase. The brain magnetic resonance imaging patient was hallmarked by extensive symmetrical...
Dysfunction of mitochondrial respiration is an increasingly recognized cause isolated hypertrophic cardiomyopathy. To gain insight into the genetic origin this condition, we used next-generation exome sequencing to identify mutations in MTO1, which encodes translation optimization 1. Two affected siblings carried a maternal c.1858dup (p.Arg620Lysfs(∗)8) frameshift and paternal c.1282G>A (p.Ala428Thr) missense mutation. A third unrelated individual was homozygous for latter change. In both...
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...
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...
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...
Primary coenzyme Q10 (CoQ10) deficiencies are rare, clinically heterogeneous disorders caused by mutations in several genes encoding proteins involved CoQ10 biosynthesis. is an essential component of the electron transport chain (ETC), where it shuttles electrons from complex I or II to III. By whole-exome sequencing, we identified five individuals carrying biallelic COQ4. The precise function human COQ4 not known, but seems play a structural role stabilizing multiheteromeric that contains...
By way of whole-exome sequencing, we identified a homozygous missense mutation in VARS2 one subject with microcephaly and epilepsy associated isolated deficiency the mitochondrial respiratory chain (MRC) complex I compound heterozygous mutations TARS2 two siblings presenting axial hypotonia severe psychomotor delay multiple MRC defects. The nucleotide variants segregated within families, were absent Single Nucleotide Polymorphism (SNP) databases are predicted to be deleterious. amount...
Mitochondrial apoptosis-inducing factor (AIF) influences the oxidative phosphorylation (OXPHOS) system and can be recruited as a mediator of cell death. Pathogenic mutations in AIFM1 gene cause severe human diseases. Clinical manifestations include inherited peripheral neuropathies, prenatal cerebral abnormalities progressive mitochondrial encephalomyopathies. In humans, rodents invertebrates, AIF deficiency results loss respiratory complexes and, therefore, impaired OXPHOS. The molecular...