A5056218699- Metabolism and Genetic Disorders
- Mitochondrial Function and Pathology
- RNA modifications and cancer
- Genomics and Rare Diseases
- RNA and protein synthesis mechanisms
- ATP Synthase and ATPases Research
- Folate and B Vitamins Research
- Genetics and Neurodevelopmental Disorders
- Neonatal Health and Biochemistry
- Genomic variations and chromosomal abnormalities
- DNA and Nucleic Acid Chemistry
- interferon and immune responses
- Amino Acid Enzymes and Metabolism
- Chemokine receptors and signaling
- Autism Spectrum Disorder Research
- Diet and metabolism studies
- Prion Diseases and Protein Misfolding
- DNA Repair Mechanisms
- Genetic Neurodegenerative Diseases
- Advanced biosensing and bioanalysis techniques
- RNA Research and Splicing
- Neurological diseases and metabolism
- Connective tissue disorders research
- Carbohydrate Chemistry and Synthesis
- Trace Elements in Health
University of Toronto
2016-2024
Hospital for Sick Children
2016-2024
SickKids Foundation
2016-2024
Synlogic (United States)
2023-2024
University of Pennsylvania
2006-2023
University Medical Center Groningen
2021
Centre Hospitalier Universitaire de Tours
2021
Inserm
2021
Université de Tours
2021
Charles University
2019
PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard care often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly inconclusive. Whole-genome (WGS) provides comprehensive platform that has the potential to streamline genetic assessments, but there are limited comparative data guide its clinical use.MethodsWe prospectively recruited 103 patients from non-genetic...
Abstract Propionic acidaemia is a rare disorder caused by defects in the propionyl-coenzyme A carboxylase α or β (PCCA PCCB) subunits that leads to an accumulation of toxic metabolites and recurrent, life-threatening metabolic decompensation events. Here we report interim analyses first-in-human, phase 1/2, open-label, dose-optimization study extension evaluating safety efficacy mRNA-3927, dual mRNA therapy encoding PCCA PCCB. As 31 May 2023, 16 participants were enrolled across 5 dose...
Methionine is an essential proteinogenic amino acid, but its excess can lead to deleterious effects. Inborn errors of methionine metabolism resulting from loss function in cystathionine β-synthase (CBS) cause classic homocystinuria (HCU), which managed by a methionine-restricted diet. Synthetic biotics are gastrointestinal tract-targeted live biotherapeutics that be engineered replicate the benefits dietary restriction. In this study, we assess whether SYNB1353, E. coli Nissle 1917...
Expansion of polyglutamine repeats in several unrelated proteins causes neurodegenerative diseases with distinct but related pathologies. To provide a model system for investigating common pathogenic features, we have examined the behavior expansions expressed Caenorhabditis elegans . The expression as green fluorescent protein (GFP)-fusion body wall muscle cells discrete cytoplasmic aggregates that appear early embryogenesis and correlates delay larval to adult development. heat shock...
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...
Mitochondrial DNA (mtDNA) variant pathogenicity interpretation has special considerations given unique features of the mtDNA genome, including maternal inheritance, heteroplasmy, threshold effect, absence splicing, and contextual effects haplogroups. Currently, there are insufficient standardized criteria for assessment, which leads to inconsistencies in clinical reporting. An international working group experts was assembled within Disease Sequence Data Resource Consortium obtained Expert...
Novel or rare variants in mitochondrial tRNA sequences may be observed after DNA analysis. Determining whether these are pathogenic is critical, but confirmation of the effect a variant on function can challenging. We have used available databases benign and variants, alignment between diverse tRNAs, structural information comparative genomics to predict impact all possible single-base deletions. The Mitochondrial Informatics Predictor (MitoTIP) through MITOMAP at www.mitomap.org. source...
Rationale: Potentially hazardous CpG-containing cell-free mitochondrial DNA (cf-mtDNA) is routinely released into the circulation and associated with morbidity mortality in critically ill patients. How body avoids inappropriate innate immune activation by cf-mtDNA remains unknown. Because red blood cells (RBCs) modulate responses scavenging chemokines, we hypothesized that RBCs may attenuate CpG-induced lung inflammation through direct of DNA.Objectives: To determine mechanisms CpG-DNA...
Abstract Single-stranded DNA or RNA sequences rich in guanine (G) can adopt non-canonical structures known as G-quadruplexes (G4). Mitochondrial (mtDNA) that are predicted to form G4 enriched on the heavy-strand and have been associated with formation of deletion breakpoints. Increasing evidence supports ability mtDNA cancer cells; however, functional roles regulating mitochondrial nucleic acid homeostasis non-cancerous cells remain unclear. Here, we demonstrate by live cell imaging...
The yeast prion [ PSI + ] provides an epigenetic mechanism for the inheritance of new phenotypes through self-perpetuating changes in protein conformation. is a nonfunctional, ordered aggregate translation termination factor Sup35p that influences Sup35 proteins to adopt same state. N-terminal region plays central role induction and propagation. C-terminal activity. function highly charged, conformationally flexible middle (M) unknown. An M deletion mutant was capable existing either or...
Current generation DNA sequencing instruments are moving closer to seamlessly genomes of entire populations as a routine part scientific investigation. However, while significant inroads have been made identifying small nucleotide variation and structural variations in that impact phenotypes interest, progress has not dramatic regarding epigenetic changes base-level damage DNA, largely due technological limitations assaying all known unknown types modifications at genome scale. Recently,...
The development and maintenance of mitochondrial heteroplasmy has important consequences for both health heredity. Previous studies using pathogenic mutations have shown considerable variability between maternally related individuals several D-loop polymorphisms suggested a relationship somatic aging. To broadly explore the variation human to clarify dynamics over course lifespan, we analyzed sequence across range ages. We utilized array-generated single-nucleotide polymorphism data that...
<h3>BACKGROUND:</h3> The Personal Genome Project Canada is a comprehensive public data resource that integrates whole genome sequencing and health information. We describe genomic variation identified in the initial recruitment cohort of 56 volunteers. <h3>METHODS:</h3> Volunteers were screened for eligibility provided informed consent open sharing. Using blood DNA, we performed all possible classes DNA variants. A genetic counsellor explained implication results to each participant....
The heavy strand of mtDNA contains two promoters with nonoverlapping functions. role the minor heavy-strand promoter (HSP2) is controversial, because has been difficult to activate in an vitro system. We have isolated HSP2 by excluding its interaction more powerful HSP1 promoter, and we find that it transcribed efficiently recombinant mtRNA polymerase mitochondrial transcription factor B2. A not required for initiation, but ability alternatively repress transcriptional unit depending on...
ATAD1 encodes Thorase, a mediator of α-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptor recycling; in this work, we characterized the phenotype resulting from mutations and developed targeted therapy both mice humans.Using exome sequencing, identified novel mutation (p.E276X) as etiology devastating neurologic disorder by hypertonia, seizures, death consanguineous family. We postulated that pathogenesis was result excessive AMPA activity designed therapeutic approach using...
Abstract Defining different genetic subtypes of autism spectrum disorder (ASD) can enable the prediction developmental outcomes. Based on minor physical and major congenital anomalies, we categorize 325 Canadian children with ASD into dysmorphic nondysmorphic subgroups. We develop a method for calculating patient-level, genome-wide rare variant score (GRVS) from whole-genome sequencing (WGS) data. GRVS is sum number variants in morphology-associated coding non-coding regions, weighted by...