A5039087857- Muscle Physiology and Disorders
- RNA Research and Splicing
- Cardiomyopathy and Myosin Studies
- RNA modifications and cancer
- Neurogenetic and Muscular Disorders Research
- Genetics and Neurodevelopmental Disorders
- Neurobiology and Insect Physiology Research
- Genetic Neurodegenerative Diseases
- Invertebrate Immune Response Mechanisms
- Ubiquitin and proteasome pathways
- Insect and Arachnid Ecology and Behavior
- Mitochondrial Function and Pathology
- RNA and protein synthesis mechanisms
- Adipose Tissue and Metabolism
- Genetics, Aging, and Longevity in Model Organisms
- Genomics and Rare Diseases
- Fuel Cells and Related Materials
- Nuclear Structure and Function
- Genetics, Bioinformatics, and Biomedical Research
- Amyotrophic Lateral Sclerosis Research
- Trypanosoma species research and implications
- Cancer Genomics and Diagnostics
- Science, Research, and Medicine
- Cardiovascular Effects of Exercise
- Cellular transport and secretion
Tufts Medical Center
2016-2025
Tufts University
2024
Wellesley College
2024
Mayo Clinic
2012
Duke University Hospital
2012
Duke Medical Center
2012
Abstract Nuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) up to 50% frontotemporal dementia (FTD) Alzheimer’s disease. In disease, pathology is predominantly observed limbic system correlates cognitive decline reduced hippocampal volume. Disruption nuclear function leads abnormal RNA splicing incorporation erroneous cryptic exons numerous transcripts including...
Abstract In mammals, dopamine 2‐like receptors are expressed in distinct pathways within the central nervous system, as well peripheral tissues. Selected neuronal D2‐like play a critical role modulating locomotor activity and, such, represent an important therapeutic target (e.g. Parkinson's disease). Previous studies have established that proteins required for (DA) neurotransmission highly conserved between mammals and fruit fly Drosophila melanogaster . These include receptor (DD2R; Hearn...
Incomplete penetrance and variable expression of hypertrophic cardiomyopathy (HCM) is well appreciated. Common genetic polymorphisms variants that may affect HCM have been predicted but are not established.We performed a case-control genomewide association study to identify common HCM-associated then asked whether such were more represented in or could explain the heterogeneity phenotypes. We identified an intronic FHOD3 variant (rs516514) associated with (odds ratio, 2.45; 95% confidence...
Pathogenic variants in HMGCR were recently linked to a limb-girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes key component of the cholesterol synthesis pathway. two other muscle diseases associated with HMGCR, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited Mendelian pattern. Statins inhibit activity generate their cholesterol-lowering effects known cause multiple types adverse on skeletal muscle, while...
Gene expression in a tissue-specific context depends on the combined efforts of epigenetic, transcriptional and post-transcriptional processes that lead to production specific proteins are important determinants cellular identity. Ribosomes central component protein biosynthesis machinery cells; however, their regulatory roles translational control gene skeletal muscle remain be defined. In genetic screen identify critical regulators myogenesis, we identified DEAD-Box RNA helicase, DDX27, is...
Mutations in MEGF10 cause early onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD), a rare congenital muscle disease, but the pathogenic mechanisms remain largely unknown. We demonstrate that short hairpin RNA (shRNA)-mediated knockdown of Megf10, as well overexpression human p.C774R mutation, leads to impaired proliferation migration C2C12 cells. Myoblasts from Megf10-/- mice Megf10-/-/mdx double knockout (dko) also show compared myoblasts wild type mdx mice, whereas...
Insect metamorphosis relies on temporal and spatial cues that are precisely controlled. Previous studies in Drosophila have shown untimely activation of genes essential to results growth defects, developmental delay death. Multiple factors exist safeguard these against dysregulated expression. The list identified negative regulators play such a role development continues expand.By using RNAi transgene-induced gene silencing coupled spatio/temporal assessment, we unraveled an important for...
Mutations in the gene encoding single transmembrane receptor multiple epidermal growth factor-like domain 10 (MEGF10) cause an autosomal recessive congenital muscle disease humans. Although mammalian MEGF10 is expressed central nervous system as well skeletal muscle, patients carrying mutations do not show symptoms of dysfunction. drpr sole Drosophila homolog human genes MEGF10, MEGF11, and MEGF12 (JEDI, PEAR). The functional domains bear striking similarities, residues affected by humans...
Next-generation sequencing is commonly used to screen for pathogenic mutations in families with Mendelian disorders, but due the pace of discoveries, gaps have widened some diseases between genetic and pathophysiological knowledge. We recruited analyzed 16 limb-girdle muscular dystrophy (LGMD) Arab descent from Saudi Arabia Sudan who did not confirmed diagnoses. The analysis included both traditional next-generation approaches. Cellular metabolic studies were performed on Pyroxd1 siRNA C2C12...
Biallelic loss‐of‐function MEGF10 mutations lead to myopathy, also known as early onset myopathy with areflexia, respiratory distress, and dysphagia (EMARDD). is expressed in muscle satellite cells, but the contribution of cell dysfunction unclear. Myofibers cells were isolated examined from Megf10 −/− wild‐type mice. A separate set mice underwent repeated intramuscular barium chloride injections. showed reduced proliferation migration, while mouse skeletal muscles impaired regeneration....
We show that a sleep-regulating, Ig-domain protein (NKT) is secreted from
Abstract Pathogenic variants in HMGCR were recently linked to a limb-girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes key component of the cholesterol synthesis pathway. two other muscle diseases associated with HMGCR, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited Mendelian pattern. mechanism linking pathogenic skeletal dysfunction is unclear. We knocked down Hmgcr mouse myoblasts, hmgcr Drosophila,...
The Drosophila smooth gene encodes an RNA binding protein which has been well conserved through evolution. To investigate the pleiotropic functions mediated by gene, we have selected and characterized two sm mutants are viable as adults yet display robust phenotypes (including a significant decrease in lifespan). Utilizing these mutants, made novel observation that disruption of smooth/CG9218 locus leads to age-dependent muscle degeneration, motor dysfunction. Histological characterization...
Abstract Introduction RNA‐binding proteins (RBPs) play an important role in skeletal muscle development and disease by regulating RNA splicing. In myotonic dystrophy type 1 (DM1), the RBP MBNL1 (muscleblind‐like) is sequestered toxic CUG repeats, leading to missplicing of targets. Mounting evidence from literature has implicated other factors pathogenesis DM1. Herein we sought evaluate functional splicing factor hnRNP L normal DM1 cells. Methods Co‐immunoprecipitation assays using hnRNPL...
Abstract Background Pathogenic mutations causing aberrant splicing are often difficult to detect. Standard variant analysis of next‐generation sequence (NGS) data focuses on canonical splice sites. Noncanonical sites more ascertain. Methods We developed a bioinformatics pipeline that screens existing NGS for potentially novel essential (PANESS) and performed pilot study family with myotonic disorder. Further analyses were via qRT‐PCR, immunoblotting, immunohistochemistry. RNAi knockdown...
MEGF10 myopathy is a rare inherited muscle disease that named after the causative gene, MEGF10. The classic phenotype, early onset myopathy, areflexia, respiratory distress and dysphagia, severe immediately life-threatening. There are no disease-modifying therapies. We performed small molecule screen follow-up studies to seek novel therapy. A primary in vitro drug assessed cellular proliferation patterns Megf10-deficient myoblasts. Secondary evaluations were on hits using myoblasts derived...
Abstract Bursicon is a hormone that modulates wing expansion, cuticle hardening, and melanization in Drosophila melanogaster. activity mediated through its cognate G protein-coupled receptor, rickets. We have developed membrane tethered bursicon construct enables spatial modulation of rickets physiology transgenic flies. Ubiquitous expression throughout development results arrest at the pupal stage. The few organisms eclose fail to undergo expansion. These phenotypes suggest inhibits...
Recessive mutations in multiple epidermal growth factor‐like domains 10 ( MEGF ) underlie a rare congenital muscle disease known as myopathy. and its Drosophila homolog Draper (Drpr) are transmembrane receptors expressed glia. Drpr deficiency is to result abnormalities flies. In the current study, flies that ubiquitously overexpress Drpr, or mouse Megf10, display developmental arrest. The phenotype reproduced with overexpression muscle, but not other tissues, during intermediate stages of...
ABSTRACT Gene expression in a tissue-specific context depends on the combined efforts of epigenetic, transcriptional and post-transcriptional processes that lead to production specific proteins are important determinants cellular identity. Ribosomes central component protein biosynthesis machinery cells; however, their regulatory roles translational control gene skeletal muscle remain be defined. In genetic screen identify critical regulators myogenesis, we identified DEAD-Box RNA helicase,...
Heterogeneous nuclear ribonucleoprotein A1 is involved in nucleic acid homeostatic functions. The encoding gene HNRNPA1 has been associated with several neuromuscular disorders including an amyotrophic lateral sclerosis-like phenotype, distal hereditary motor neuropathy, multisystem proteinopathy, and various myopathies. We report two unrelated individuals monoallelic stop loss variants affecting the same codon of HNRNPA1.