2,074 results on '"Tarnopolsky, Mark A"'
Search Results
2. Single nuclei profiling identifies cell specific markers of skeletal muscle aging, frailty, and senescence.
- Author
-
Perez, Kevin, Ciotlos, Serban, McGirr, Julia, Limbad, Chandani, Doi, Ryosuke, Nederveen, Joshua, Nilsson, Mats, Winer, Daniel, Evans, William, Tarnopolsky, Mark, Campisi, Judith, and Melov, Simon
- Subjects
aging ,muscle ,sarcopenia ,senescence ,transcriptomics ,Aged ,Humans ,Sarcopenia ,Frailty ,Aging ,Muscle ,Skeletal ,Inflammation ,Frail Elderly - Abstract
Aging is accompanied by a loss of muscle mass and function, termed sarcopenia, which causes numerous morbidities and economic burdens in human populations. Mechanisms implicated in age-related sarcopenia or frailty include inflammation, muscle stem cell depletion, mitochondrial dysfunction, and loss of motor neurons, but whether there are key drivers of sarcopenia are not yet known. To gain deeper insights into age-related muscle loss, we performed transcriptome profiling on lower limb muscle biopsies from 72 young, elderly, and frail human subjects using bulk RNA-seq (N = 72) and single-nuclei RNA-seq (N = 17). This combined approach revealed changes in gene expression that occur with age and frailty in multiple cell types comprising mature skeletal muscle. Notably, we found increased expression of the genes MYH8 and PDK4, and decreased expression of the gene IGFN1, in aged muscle. We validated several key genes changes in fixed human muscle tissue using digital spatial profiling. We also identified a small population of nuclei that express CDKN1A, present only in aged samples, consistent with p21cip1-driven senescence in this subpopulation. Overall, our findings identify unique cellular subpopulations in aged and sarcopenic skeletal muscle, which will facilitate the development of new therapeutic strategies to combat age-related frailty.
- Published
- 2022
3. Secondary mitochondrial dysfunction across the spectrum of hereditary and acquired muscle disorders
- Author
-
Mak, Gloria, Tarnopolsky, Mark, and Lu, Jian-Qiang
- Published
- 2024
- Full Text
- View/download PDF
4. Metabolic features of treatment-refractory major depressive disorder with suicidal ideation
- Author
-
Pan, Lisa A., Naviaux, Jane C., Wang, Lin, Li, Kefeng, Monk, Jonathan M., Lingampelly, Sai Sachin, Segreti, Anna Maria, Bloom, Kaitlyn, Vockley, Jerry, Tarnopolsky, Mark A., Finegold, David N., Peters, David G., and Naviaux, Robert K.
- Published
- 2023
- Full Text
- View/download PDF
5. Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for patients with rare disease in a publicly funded health care system: A prospective cohort study
- Author
-
Boycott, Kym, Brudno, Michael, Bernier, Francois, van Karnebeek, Clara, Dyment, David, Kernohan, Kristin, Innes, Micheil, Lamont, Ryan, Parboosingh, Jillian, Marshall, Deborah, Marshall, Christian, Mendoza, Roberto, Dowling, James, Hayeems, Robin, Knoppers, Bartha, Lehman, Anna, Mostafavi, Sara, Hartley, Taila, Acker, Meryl, Fooks, Katharine, Gillespie, Meredith K., Price, E. Magda, Graham, Ian D., White-Brown, Alexandre, MacKay, Layla, Macdonald, Stella K., Brady, Lauren, Hui, Angela Y., Andrews, Joseph D., Chowdhury, Ashfia, Wall, Erika, Soubry, Élisabeth, Ediae, Grace U., Rojas, Samantha, Assamad, Daniel, Tarnopolsky, Mark, Sawyer, Sarah L., Chisholm, Caitlin, Lemire, Gabrielle, Amburgey, Kimberly, Lazier, Joanna, Mendoza-Londono, Roberto, Dowling, James J., Balci, Tugce B., Armour, Christine M., Bhola, Priya T., Costain, Gregory, Dupuis, Lucie, Carter, Melissa, Badalato, Lauren, Richer, Julie, Boswell-Patterson, Christie, Kannu, Peter, Cordeiro, Dawn, Warman-Chardon, Jodi, Graham, Gail, Siu, Victoria Mok, Cytrynbaum, Cheryl, Rusnak, Alison, Aul, Ritu B., Yoon, Grace, Gonorazky, Hernan, McNiven, Vanda, Mercimek-Andrews, Saadet, Guerin, Andrea, Deshwar, Ashish R., Marwaha, Ashish, Weksberg, Rosanna, Karp, Natalya, Campbell, Maggie, Al-Qattan, Sarah, Shuen, Andrew Y., Inbar-Feigenberg, Michal, Cohn, Ronald, Szuto, Anna, Inglese, Cara, Poirier, Myriam, Chad, Lauren, Potter, Beth, and Boycott, Kym M.
- Published
- 2024
- Full Text
- View/download PDF
6. An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids.
- Author
-
Ferdinandusse, Sacha, McWalter, Kirsty, Te Brinke, Heleen, IJlst, Lodewijk, Mooijer, Petra M, Ruiter, Jos PN, van Lint, Alida EM, Pras-Raves, Mia, Wever, Eric, Millan, Francisca, Guillen Sacoto, Maria J, Begtrup, Amber, Tarnopolsky, Mark, Brady, Lauren, Ladda, Roger L, Sell, Susan L, Nowak, Catherine B, Douglas, Jessica, Tian, Cuixia, Ulm, Elizabeth, Perlman, Seth, Drack, Arlene V, Chong, Karen, Martin, Nicole, Brault, Jennifer, Brokamp, Elly, Toro, Camilo, Gahl, William A, Macnamara, Ellen F, Wolfe, Lynne, Undiagnosed Diseases Network, Waisfisz, Quinten, Zwijnenburg, Petra JG, Ziegler, Alban, Barth, Magalie, Smith, Rosemarie, Ellingwood, Sara, Gaebler-Spira, Deborah, Bakhtiari, Somayeh, Kruer, Michael C, van Kampen, Antoine HC, Wanders, Ronald JA, Waterham, Hans R, Cassiman, David, and Vaz, Frédéric M
- Subjects
Undiagnosed Diseases Network ,Humans ,Spastic Paraplegia ,Hereditary ,Ethers ,Aldehyde Oxidoreductases ,Lipids ,Phenotype ,Neurosciences ,Genetics ,Clinical Research ,Pediatric ,2.1 Biological and endogenous factors ,Neurological ,Genetics & Heredity ,Clinical Sciences - Abstract
PurposeIn this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).MethodsFollowing next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.ResultsAll patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.ConclusionHeterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.
- Published
- 2021
7. Cylindrical spirals and other concentric structures of skeletal muscle in patients with neurological diseases
- Author
-
Fournier, Jeffrey E., Mak, Gloria, Gordon, Katerina, Glogauer, Judah, Fareez, Faiha, Provias, John, Tarnopolsky, Mark A., and Lu, Jian-Qiang
- Published
- 2023
- Full Text
- View/download PDF
8. Results from a 3-year Non-interventional, Observational Disease Monitoring Program in Adults with GNE Myopathy
- Author
-
Lochmüller, Hanns, Behin, Anthony, Tournev, Ivailo, Tarnopolsky, Mark, Horváth, Rita, Pogoryelova, Oksana, Shah, Jinay, Koutsoukos, Tony, Skrinar, Alison, Kakkis, Emil, Bedrosian, Camille L, and Mozaffar, Tahseen
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Brain Disorders ,Clinical Research ,Clinical Trials and Supportive Activities ,Adult ,Bulgaria ,Distal Myopathies ,Female ,Humans ,Lower Extremity ,Male ,Middle Aged ,Muscle Strength ,Muscle Weakness ,Muscle ,Skeletal ,Prospective Studies ,Young Adult ,Myopathies ,muscular diseases ,muscle weakness ,N-acetylneuraminic acid - Abstract
BackgroundGNE myopathy is a rare, autosomal recessive, muscle disease caused by mutations in GNE and is characterized by rimmed vacuoles on muscle biopsy and progressive distal to proximal muscle weakness.ObjectiveInvestigate the clinical presentation and progression of GNE myopathy.MethodsThe GNE Myopathy Disease Monitoring Program was an international, prospective, observational study in subjects with GNE myopathy. Muscle strength was assessed with hand-held dynamometry (HHD), with upper extremity (UE) and lower extremity (LE) composite scores reflecting upper and lower extremity muscle groups, respectively. The GNE myopathy-Functional Activity Scale (GNEM-FAS) was used to further assess impairment in mobility, upper extremity function, and self-care.ResultsEighty-seven of 101 enrolled subjects completed the trial until study closure by the sponsor; 60 completed 36 months. Mean (SD) HHD UE composite score decreased from 34.3 kg (32.0) at baseline to 29.4 kg (32.6) kg at month 36 (LS mean change [95%CI]: -3.8 kg [-5.9, -1.7]; P = 0.0005). Mean (SD) HHD LE composite score decreased from 32.0 kg (34.1) at baseline to 25.5 kg (31.2) at month 36 (LS mean change [95%CI]: -4.9 [-7.7, -2.2]; P = 0.0005). GNEM-FAS scores were more severe at baseline in subjects who walked
- Published
- 2021
9. Skeletal Muscle Mitochondrial Morphology Negatively Affected in Mice Lacking Xin
- Author
-
Martin, Grace, primary, Al-Sajee, Dhuha, additional, Gingrich, Molly, additional, Chattha, Rimsha, additional, Akcan, Michael, additional, Monaco, Cynthia M.F., additional, Hughes, Meghan C, additional, Perry, Christopher G.R., additional, Rebalka, Irena A, additional, Tarnopolsky, Mark A, additional, and Hawke, Thomas James, additional
- Published
- 2024
- Full Text
- View/download PDF
10. Biallelic mutations in SUPV3L1 cause an inherited neurodevelopmental disorder with variable leukodystrophy due to aberrant mitochondrial double stranded RNA processing
- Author
-
Green, Lydia, primary, Hamilton, Noémie, additional, Elpidorou, Marilena, additional, Maroofian, Reza, additional, Douglas, Andrew G.L., additional, Õunap, Katrin, additional, Rose, Ailsa M.S., additional, Harris, Erica L., additional, Elworthy, Stone, additional, Renshaw, Stephen A., additional, Low, Elizabeth C., additional, Dockrell, David H., additional, Tveten, Kristian, additional, Wells, Geoffrey, additional, Harris, Sarah A., additional, Al-Maawali, Almundher, additional, Al-Thihli, Khalid, additional, Al-Zuhaibi, Sana, additional, Futaisi, Amna Al, additional, Calame, Daniel, additional, Chinn, Ivan, additional, Fisher, Kristen S., additional, Sa, Mario, additional, Warren, Daniel, additional, Zamani, Mina, additional, Sadeghian, Saeid, additional, Azizimalamiri, Reza, additional, Galehdari, Hamid, additional, Shariati, Gholamreza, additional, Seifi, Tahere, additional, Zaki, Maha S., additional, Afzal, Erum, additional, Tarnopolsky, Mark A., additional, Brady, Lauren, additional, Zuchner, Stephan L., additional, Efthymiou, Stephanie, additional, Scardamaglia, Annarita, additional, Houlden, Henry, additional, Wakeling, Emma, additional, Prabhakar, Prab, additional, Roca-Bayerri, Carla, additional, Rice, Gillian I., additional, Prouteau, Clément, additional, Bris, Céline, additional, Tessarech, Marine, additional, Sandvig, Inger, additional, Sheridan, Eamonn G., additional, Johnson, Colin A., additional, Livingston, John H., additional, Crow, Yanick J., additional, and Poulter, James A., additional
- Published
- 2024
- Full Text
- View/download PDF
11. A phase 3 randomized study evaluating sialic acid extended-release for GNE myopathy
- Author
-
Lochmüller, Hanns, Behin, Anthony, Caraco, Yoseph, Lau, Heather, Mirabella, Massimiliano, Tournev, Ivailo, Tarnopolsky, Mark, Pogoryelova, Oksana, Woods, Catherine, Lai, Alexander, Shah, Jinay, Koutsoukos, Tony, Skrinar, Alison, Mansbach, Hank, Kakkis, Emil, and Mozaffar, Tahseen
- Subjects
Clinical Research ,Clinical Trials and Supportive Activities ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Delayed-Action Preparations ,Distal Myopathies ,Double-Blind Method ,Female ,Humans ,Male ,Middle Aged ,Muscle Strength ,Muscle ,Skeletal ,N-Acetylneuraminic Acid ,Treatment Outcome ,Young Adult ,Clinical Sciences ,Neurosciences ,Cognitive Sciences ,Neurology & Neurosurgery - Abstract
ObjectiveTo investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), a treatment intended to replace deficient sialic acid, in patients with GNE myopathy.MethodsUX001-CL301 was a phase 3, double-blind, placebo-controlled, randomized, international study evaluating the efficacy and safety of Ace-ER in patients with GNE myopathy. Participants who could walk ≥200 meters in a 6-minute walk test at screening were randomized 1:1, and stratified by sex, to receive Ace-ER 6 g/d or placebo for 48 weeks and assessed every 8 weeks. The primary endpoint was change in muscle strength over 48 weeks measured by upper extremity composite (UEC) score. Key secondary endpoints included change in lower extremity composite (LEC) score, knee extensor strength, and GNE myopathy-Functional Activity Scale (GNEM-FAS) mobility domain score. Safety assessments included adverse events (AEs), vital signs, and clinical laboratory results.ResultsEighty-nine patients were randomized (Ace-ER n = 45; placebo n = 44). Change from baseline to week 48 for UEC score between treatments did not differ (least square mean [LSM] Ace-ER -2.25 kg vs placebo -2.99 kg; LSM difference confidence interval [CI] 0.74 [-1.61 to 3.09]; p = 0.5387). At week 48, there was no significant difference between treatments for the change in key secondary endpoints: LEC LSM difference (CI) -1.49 (-5.83 to 2.86); knee extension strength -0.40 (-2.38 to 1.58); and GNEM-FAS mobility domain score -0.72 (-2.01 to 0.57). Gastrointestinal events were the most common AEs.ConclusionsAce-ER was not superior to placebo in improving muscle strength and function in patients with GNE myopathy.Classification of evidenceThis study provides Class I evidence that for patients with GNE myopathy, Ace-ER does not improve muscle strength compared to placebo.
- Published
- 2019
12. Genetic, structural and clinical analysis of spastic paraplegia 4
- Author
-
Varghaei, Parizad, Estiar, Mehrdad A., Ashtiani, Setareh, Veyron, Simon, Mufti, Kheireddin, Leveille, Etienne, Yu, Eric, Spiegelman, Dan, Rioux, Marie-France, Yoon, Grace, Tarnopolsky, Mark, Boycott, Kym M., Dupre, Nicolas, Suchowersky, Oksana, Trempe, Jean-François, Rouleau, Guy A., and Gan-Or, Ziv
- Published
- 2022
- Full Text
- View/download PDF
13. Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance
- Author
-
Lebeau, Paul F., Byun, Jae Hyun, Platko, Khrystyna, Saliba, Paul, Sguazzin, Matthew, MacDonald, Melissa E., Paré, Guillaume, Steinberg, Gregory R., Janssen, Luke J., Igdoura, Suleiman A., Tarnopolsky, Mark A., Wayne Chen, S. R., Seidah, Nabil G., Magolan, Jakob, and Austin, Richard C.
- Published
- 2022
- Full Text
- View/download PDF
14. Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy
- Author
-
Kim, Hong Joo, Mohassel, Payam, Donkervoort, Sandra, Guo, Lin, O’Donovan, Kevin, Coughlin, Maura, Lornage, Xaviere, Foulds, Nicola, Hammans, Simon R., Foley, A. Reghan, Fare, Charlotte M., Ford, Alice F., Ogasawara, Masashi, Sato, Aki, Iida, Aritoshi, Munot, Pinki, Ambegaonkar, Gautam, Phadke, Rahul, O’Donovan, Dominic G., Buchert, Rebecca, Grimmel, Mona, Töpf, Ana, Zaharieva, Irina T., Brady, Lauren, Hu, Ying, Lloyd, Thomas E., Klein, Andrea, Steinlin, Maja, Kuster, Alice, Mercier, Sandra, Marcorelles, Pascale, Péréon, Yann, Fleurence, Emmanuelle, Manzur, Adnan, Ennis, Sarah, Upstill-Goddard, Rosanna, Bello, Luca, Bertolin, Cinzia, Pegoraro, Elena, Salviati, Leonardo, French, Courtney E., Shatillo, Andriy, Raymond, F. Lucy, Haack, Tobias B., Quijano-Roy, Susana, Böhm, Johann, Nelson, Isabelle, Stojkovic, Tanya, Evangelista, Teresinha, Straub, Volker, Romero, Norma B., Laporte, Jocelyn, Muntoni, Francesco, Nishino, Ichizo, Tarnopolsky, Mark A., Shorter, James, Bönnemann, Carsten G., and Taylor, J. Paul
- Published
- 2022
- Full Text
- View/download PDF
15. Functional characterization of variants of unknown significance in a spinocerebellar ataxia patient using an unsupervised machine learning pipeline
- Author
-
Nath, Siddharth, Caron, Nicholas S., May, Linda, Gluscencova, Oxana B., Kolesar, Jill, Brady, Lauren, Kaufman, Brett A., Boulianne, Gabrielle L., Rodriguez, Amadeo R., Tarnopolsky, Mark A., and Truant, Ray
- Published
- 2022
- Full Text
- View/download PDF
16. Normal to enhanced intrinsic mitochondrial respiration in skeletal muscle of middle- to older-aged women and men with uncomplicated type 1 diabetes
- Author
-
Monaco, Cynthia M. F., Tarnopolsky, Mark A., Dial, Athan G., Nederveen, Joshua P., Rebalka, Irena A., Nguyen, Maria, Turner, Lauren V., Perry, Christopher G. R., Ljubicic, Vladimir, and Hawke, Thomas J.
- Published
- 2021
- Full Text
- View/download PDF
17. Clinical practice guidelines for glycogen storage disease V & VII (McArdle disease and Tarui disease) from an international study group
- Author
-
Bali, Deeksha, Godfrey, Richard, Haller, Ronald, Kishnani, Priya, Laforêt, Pascal, Løkken, Nicoline, Musumeci, Olimpia, Santalla, Alfredo, Tarnopolsky, Mark, Toscano, Antonio, Vissing, John, Voermans, Nicol, Wakelin, Andrew, Lucia, Alejandro, Martinuzzi, Andrea, Nogales-Gadea, Gisela, Quinlivan, Ros, and Reason, Stacey
- Published
- 2021
- Full Text
- View/download PDF
18. Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial
- Author
-
Sebok, Agnes, Pestronk, Alan, Dominovic-Kovacevic, Aleksandra, Khan, Aneal, Koritnik, Blaž, Tard, Celine, Lindberg, Christopher, Quinn, Colin, Kornblum, Cornelia, Eldridge, Crystal, Bodkin, Cynthia, Reyes-Leiva, David, Hughes, Derralynn, Stefanescu, Ela, SALORT-CAMPANA, Emmanuelle, Butler, Ernest, Bouhour, Francoise, Kim, Gee, Konstantinos Papadimas, George, Parenti, Giancarlo, Bartosik-Psujek, Halina, Kushlaf, Hani, Akihiro, Hashiguchi, Lau, Heather, Pedro, Helio, Andersen, Henning, Amartino, Hernan, Shiraishi, Hideaki, Kobayashi, Hiroshi, Tarnev, Ivaylo, Vengoechea, Jaime, Avelar, Jennifer, Shin, Jin-Hong, Cauci, Jonathan, Alonso-Pérez, Jorge, Janszky, Jozsef, Berthy, Julie, Gutschmidt, Kristina, Claeys, Kristl, Judit Molnar, Maria, Wencel, Marie, Tarnopolsky, Mark, Dimachkie, Mazen, Tchan, Michel, Freimer, Miriam, Longo, Nicola, Vidal-Fernandez, Nuria, Musumeci, Olimpia, Goker-Alpan, Ozlem, Deegan, Patrick, Clemens, Paula R., Roxburgh, Richard, Henderson, Robert, Hopkin, Robert, Sacconi, Sabrina, Fecarotta, Simona, Attarian, Shahram, Wenninger, Stephan, Dearmey, Stephanie, Hiwot, Tarekegn, Burrow, Thomas, Ruck, Tobias, Sawada, Tomo, Laszlo, Vescei, Löscher, Wolfgang, Chien, Yin-Hsiu, Schoser, Benedikt, Roberts, Mark, Byrne, Barry J, Sitaraman, Sheela, Jiang, Hai, Laforêt, Pascal, Toscano, Antonio, Castelli, Jeff, Díaz-Manera, Jordi, Goldman, Mitchell, van der Ploeg, Ans T, Bratkovic, Drago, Kuchipudi, Srilakshmi, Mozaffar, Tahseen, and Kishnani, Priya S
- Published
- 2021
- Full Text
- View/download PDF
19. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial
- Author
-
Behin, Anthony, Boentert, Matthias, Carvalho, Gerson, Chahin, Nizar, Charrow, Joel, Deegan, Patrick, Durmus Tekce, Hacer, Duval, Fanny, Genge, Angela, Gutmann, Ludwig, Henderson, Robert D, Hennermann, Julia B, Hiwot, Tarekegn, Hughes, Derralynn, Karaa, Amel, Karam, Chafic, Kautzky-Willer, Alexandra, Komaki, Hirofumi, Laforet, Pascal, Longo, Nicola, Malinova, Vera, Maré, Ricardo, Maxit, Clarisa, Mengel, Eugen, Moggio, Maurizio Gualtiero, Molnár, Mária Judit, Mongini, Tiziana Enrica, Nadaj-Pakleza, Aleksandra, Nascimento Osorio, Andres, Noury, Jean-Baptiste, Oliveira, Acary Souza Bulle, Parman, Yesim, Pena, Loren, Remiche, Gauthier, Sciacco, Monica, Shieh, Perry B, Smith, Cheryl, Stulnig, Thomas, Taithe, Frederic, Tard, Céline, Tarnopolsky, Mark, Vorgerd, Matthias, Whitley, Chester, Young, Peter, Alonso-Pérez, Jorge, Altemus, Patricia, Aubé-Nathier, Anne-Catherine, Avelar, Jennifer B, Bailey, Carrie, Bekircan-Kurt, Can Ebru, Billy, Jenny, Boschi, Silvia, Brown, Kathryn E, Carrera Garcia, Laura, Chase, Lauren, Cirne, Hamilton, Danjoux, Loïc, Davion, Jean-Baptiste, DeArmey, Stephanie, Fedotova, Ekaterina, Gandolfo, Eve, Grosz, Zoltan, Guellec, Dewi, Guettsches, Anne-Katrin, Guglieri, Michela, Hatcher, Erin, Helms, Sina, Hufgard-Leitner, Miriam, Klyushnikov, Sergey A., Langton, Jacqui, Linková, Lenka, Mavroudakis, Nicolas, Mazurová, Stella, Mori, Madoka, Müller-Miny, Louisa, Musumeci, Olimpia, Nance, Christopher S, Natera-de Benito, Daniel, Neel, Robert, Niizawa, Gabriela A, Noll, Lauren, Ortega, Erik, Pasnoor, Mamatha, Pautot, Vivien, Potulska-Chromik, Anna, Pugliese, Alessia, Questienne, Claire, Ramos Lopes, Margarida, Reyes-Leiva, David, Riedl, Michaela, Rugiero, Marcelo Francisco, Salort-Campana, Emmanuelle, Sgobbi Souza, Paulo Victor, Sole, Guilhem, Solera, Luca, Souto Lopes, Suzara, Specht, Sabine, Statland, Jeffrey, Swenson, Andrea, Tan, Chong Yew, Tizon, Sónia, van der Beek, N A M E, van Kooten, Harmke A., Wencel, Marie, Wenninger, Stephan, Zagnoli, Fabien, Diaz-Manera, Jordi, Kishnani, Priya S, Kushlaf, Hani, Ladha, Shafeeq, Mozaffar, Tahseen, Straub, Volker, Toscano, Antonio, van der Ploeg, Ans T, Berger, Kenneth I, Clemens, Paula R, Chien, Yin-Hsiu, Day, John W, Illarioshkin, Sergey, Roberts, Mark, Attarian, Shahram, Borges, Joao Lindolfo, Bouhour, Francoise, Choi, Young Chul, Erdem-Ozdamar, Sevim, Goker-Alpan, Ozlem, Kostera-Pruszczyk, Anna, Haack, Kristina An, Hug, Christopher, Huynh-Ba, Olivier, Johnson, Judith, Thibault, Nathan, Zhou, Tianyue, Dimachkie, Mazen M, and Schoser, Benedikt
- Published
- 2021
- Full Text
- View/download PDF
20. Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for patients with rare disease in a publicly funded health care system: A prospective cohort study
- Author
-
Hartley, Taila, primary, Marshall, Deborah, additional, Acker, Meryl, additional, Fooks, Katharine, additional, Gillespie, Meredith K., additional, Price, E. Magda, additional, Graham, Ian D., additional, White-Brown, Alexandre, additional, MacKay, Layla, additional, Macdonald, Stella K., additional, Brady, Lauren, additional, Hui, Angela Y., additional, Andrews, Joseph D., additional, Chowdhury, Ashfia, additional, Wall, Erika, additional, Soubry, Élisabeth, additional, Ediae, Grace U., additional, Rojas, Samantha, additional, Assamad, Daniel, additional, Dyment, David, additional, Tarnopolsky, Mark, additional, Sawyer, Sarah L., additional, Chisholm, Caitlin, additional, Lemire, Gabrielle, additional, Amburgey, Kimberly, additional, Lazier, Joanna, additional, Mendoza-Londono, Roberto, additional, Dowling, James J., additional, Balci, Tugce B., additional, Armour, Christine M., additional, Bhola, Priya T., additional, Costain, Gregory, additional, Dupuis, Lucie, additional, Carter, Melissa, additional, Badalato, Lauren, additional, Richer, Julie, additional, Boswell-Patterson, Christie, additional, Kannu, Peter, additional, Cordeiro, Dawn, additional, Warman-Chardon, Jodi, additional, Graham, Gail, additional, Siu, Victoria Mok, additional, Cytrynbaum, Cheryl, additional, Rusnak, Alison, additional, Aul, Ritu B., additional, Yoon, Grace, additional, Gonorazky, Hernan, additional, McNiven, Vanda, additional, Mercimek-Andrews, Saadet, additional, Guerin, Andrea, additional, Deshwar, Ashish R., additional, Marwaha, Ashish, additional, Weksberg, Rosanna, additional, Karp, Natalya, additional, Campbell, Maggie, additional, Al-Qattan, Sarah, additional, Shuen, Andrew Y., additional, Inbar-Feigenberg, Michal, additional, Cohn, Ronald, additional, Szuto, Anna, additional, Inglese, Cara, additional, Poirier, Myriam, additional, Chad, Lauren, additional, Potter, Beth, additional, Boycott, Kym M., additional, Hayeems, Robin, additional, Boycott, Kym, additional, Brudno, Michael, additional, Bernier, Francois, additional, van Karnebeek, Clara, additional, Kernohan, Kristin, additional, Innes, Micheil, additional, Lamont, Ryan, additional, Parboosingh, Jillian, additional, Marshall, Christian, additional, Mendoza, Roberto, additional, Dowling, James, additional, Knoppers, Bartha, additional, Lehman, Anna, additional, and Mostafavi, Sara, additional
- Published
- 2024
- Full Text
- View/download PDF
21. Lien possible entre rhabdomyolyse et vaccin anti-SRAS-CoV-2 a ARNm chez une patiente porteuse d'une mutation du gene RYR1
- Author
-
Salter, Brittany, Jessome, Matthew, Tarnopolsky, Mark, and Yousuf, Haroon
- Subjects
Vaccination ,Mediation ,Health - Abstract
Une femme de 30 ans a consulte a l'hopital 8 jours apres avoir recu sa seconde dose de vaccin anti-SRAS-CoV-2 a ARNm de Moderna. Le lendemain de sa vaccination, elle [...]
- Published
- 2022
- Full Text
- View/download PDF
22. Possible association between rhabdomyolysis and mRNA SARS-CoV-2 vaccination in a patient with RYR1 gene mutation
- Author
-
Salter, Brittany, Jessome, Matthew, Tarnopolsky, Mark, and Yousuf, Haroon
- Subjects
Gene mutations -- Case studies ,Rhabdomyolysis -- Case studies -- Risk factors ,Health - Abstract
A 30-year-old woman presented to hospital 8 days after vaccination against SARS-CoV-2 with the second dose of the Moderna mRNA vaccine. One day postvaccination, she noted flu-like symptoms, including chills [...]
- Published
- 2022
- Full Text
- View/download PDF
23. Metabolic Myopathies
- Author
-
Tarnopolsky, Mark A.
- Published
- 2022
- Full Text
- View/download PDF
24. Common data elements for clinical research in mitochondrial disease: a National Institute for Neurological Disorders and Stroke project
- Author
-
Karaa, Amel, Rahman, Shamima, Lombès, Anne, Yu‐Wai‐Man, Patrick, Sheikh, Muniza K, Alai‐Hansen, Sherita, Cohen, Bruce H, Dimmock, David, Emrick, Lisa, Falk, Marni J, McCormack, Shana, Mirsky, David, Moore, Tony, Parikh, Sumit, Shoffner, John, Taivassalo, Tanja, Tarnopolsky, Mark, Tein, Ingrid, Odenkirchen, Joanne C, Goldstein, Amy, and Participants:, on behalf of the Mito Working Group Member
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Brain Disorders ,Neurosciences ,Biomedical Research ,Common Data Elements ,Data Collection ,Humans ,Mitochondrial Diseases ,National Institute of Neurological Disorders and Stroke (U.S.) ,Nervous System Diseases ,Research Design ,Stroke ,United States ,Mito Working Group Member Participants: ,Genetics & Heredity ,Genetics ,Clinical sciences - Abstract
ObjectivesThe common data elements (CDE) project was developed by the National Institute of Neurological Disorders and Stroke (NINDS) to provide clinical researchers with tools to improve data quality and allow for harmonization of data collected in different research studies. CDEs have been created for several neurological diseases; the aim of this project was to develop CDEs specifically curated for mitochondrial disease (Mito) to enhance clinical research.MethodsNine working groups (WGs), composed of international mitochondrial disease experts, provided recommendations for Mito clinical research. They initially reviewed existing NINDS CDEs and instruments, and developed new data elements or instruments when needed. Recommendations were organized, internally reviewed by the Mito WGs, and posted online for external public comment for a period of eight weeks. The final version was again reviewed by all WGs and the NINDS CDE team prior to posting for public use.ResultsThe NINDS Mito CDEs and supporting documents are publicly available on the NINDS CDE website ( https://commondataelements.ninds.nih.gov/ ), organized into domain categories such as Participant/Subject Characteristics, Assessments, and Examinations.ConclusionWe developed a comprehensive set of CDE recommendations, data definitions, case report forms (CRFs), and guidelines for use in Mito clinical research. The widespread use of CDEs is intended to enhance Mito clinical research endeavors, including natural history studies, clinical trial design, and data sharing. Ongoing international collaboration will facilitate regular review, updates and online publication of Mito CDEs, and support improved consistency of data collection and reporting.
- Published
- 2017
25. Duvoglustat HCl Increases Systemic and Tissue Exposure of Active Acid α-Glucosidase in Pompe Patients Co-administered with Alglucosidase α
- Author
-
Kishnani, Priya, Tarnopolsky, Mark, Roberts, Mark, Sivakumar, Kumarswamy, Dasouki, Majed, Dimachkie, Mazen M, Finanger, Erika, Goker-Alpan, Ozlem, Guter, Karl A, Mozaffar, Tahseen, Pervaiz, Muhammad Ali, Laforet, Pascal, Levine, Todd, Adera, Matthews, Lazauskas, Richard, Sitaraman, Sheela, Khanna, Richie, Benjamin, Elfrida, Feng, Jessie, Flanagan, John J, Barth, Jay, Barlow, Carrolee, Lockhart, David J, Valenzano, Kenneth J, Boudes, Pol, Johnson, Franklin K, and Byrne, Barry
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Rare Diseases ,Chronic Liver Disease and Cirrhosis ,Digestive Diseases ,Liver Disease ,5.1 Pharmaceuticals ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Development of treatments and therapeutic interventions ,1-Deoxynojirimycin ,Administration ,Oral ,Adult ,Drug Administration Schedule ,Drug Synergism ,Drug Therapy ,Combination ,Enzyme Replacement Therapy ,Female ,Glycogen Storage Disease Type II ,Humans ,Infusions ,Intravenous ,Lysosomes ,Male ,Middle Aged ,Muscle ,Skeletal ,Patient Safety ,Treatment Outcome ,alpha-Glucosidases ,Pompe disease ,enzyme replacement therapy ,pharmacokinetics ,pharmacological chaperone ,Biological Sciences ,Technology ,Medical and Health Sciences ,Biotechnology ,Genetics ,Clinical sciences ,Medical biotechnology - Abstract
Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid α-glucosidase (GAA) deficiency, which leads to the lysosomal storage disorder Pompe disease, which is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. The current standard of care is enzyme replacement therapy with recombinant human GAA (alglucosidase alfa [AA], Genzyme). Based on preclinical data, oral co-administration of duvoglustat HCl with AA increases exposure of active levels in plasma and skeletal muscles, leading to greater substrate reduction in muscle. This phase 2a study consisted of an open-label, fixed-treatment sequence that evaluated the effect of single oral doses of 50 mg, 100 mg, 250 mg, or 600 mg duvoglustat HCl on the pharmacokinetics and tissue levels of intravenously infused AA (20 mg/kg) in Pompe patients. AA alone resulted in increases in total GAA activity and protein in plasma compared to baseline. Following co-administration with duvoglustat HCl, total GAA activity and protein in plasma were further increased 1.2- to 2.8-fold compared to AA alone in all 25 Pompe patients; importantly, muscle GAA activity was increased for all co-administration treatments from day 3 biopsy specimens. No duvoglustat-related adverse events or drug-related tolerability issues were identified.
- Published
- 2017
26. Cardiopulmonary Exercise Testing Reflects Improved Exercise Capacity in Response to Treatment in Morquio A Patients: Results of a 52-Week Pilot Study of Two Different Doses of Elosulfase Alfa
- Author
-
Berger, Kenneth I, Burton, Barbara K, Lewis, Gregory D, Tarnopolsky, Mark, Harmatz, Paul R, Mitchell, John J, Muschol, Nicole, Jones, Simon A, Sutton, V Reid, Pastores, Gregory M, Lau, Heather, Sparkes, Rebecca, and Shaywitz, Adam J
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Clinical Trials and Supportive Activities ,Lung ,Clinical Research ,Evaluation of treatments and therapeutic interventions ,6.7 Physical ,6.1 Pharmaceuticals ,Cardiopulmonary exercise test ,Elosulfase alfa ,Endurance ,Enzyme replacement therapy ,Exercise capacity ,Mucopolysaccharidosis IVA ,Clinical sciences - Abstract
OBJECTIVE:To assess impact of a 52-week elosulfase alfa enzyme replacement therapy (ERT) on exercise capacity in Morquio A patients and analyze cardiorespiratory and metabolic function during exercise to uncover exercise limitations beyond skeletal abnormalities. METHODS:Morquio A patients aged ≥7 years, able to walk >200 m in the 6-minute walk test (6MWT), received elosulfase alfa 2.0 mg/kg/week (N = 15) or 4.0 mg/kg/week (N = 10) for 52 weeks in the randomized, double-blind MOR-008 study ( ClinicalTrials.gov NCT01609062) and its extension. Exercise capacity was assessed by 6MWT, 3-minute stair climb test (3MSCT), and cardiopulmonary exercise test (CPET; N = 15 dosage groups combined). RESULTS:Changes over 52 weeks in 6MWT and 3MSCT were minimal. Baseline CPET results showed impaired weight-adjusted peak oxygen uptake (VO2), partly attributable to inability to increase tidal volume during exercise. CPET measures of exercise function showed significant improvement at 25 and/or 52 weeks in exercise duration, peak workload, O2 pulse, and peak tidal volume (% increases in duration, 16.9 (P = 0.0045) and 9.4 (P = 0.0807); peak workload, 26.5 (P = 0.0026) and 21.2 (P = 0.0132); O2 pulse, 10.7 (P = 0.0187) and 2.3 (P = 0.643); peak tidal volume, 11.7 (P = 0.1117) and 29.1 (P = 0.0142)). In addition, decreased VO2/work ratio was noted (% decrease -7.6 [-11.9, 1.3] and -9.2 [-25.7, 5.1]), indicating performance of work at reduced oxygen cost. CONCLUSIONS:CPET uncovers limitation in exercise capacity in Morquio A related to reduced lung function. ERT improves exercise capacity and efficiency of oxygen utilization, not attributable to changes in cardiac or pulmonary function. Further study of the long-term impact of ERT on exercise capacity and the clinical relevance of the observed changes is warranted.
- Published
- 2017
27. Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism
- Author
-
Harms, Frederike Leonie, Girisha, Katta M, Hardigan, Andrew A, Kortüm, Fanny, Shukla, Anju, Alawi, Malik, Dalal, Ashwin, Brady, Lauren, Tarnopolsky, Mark, Bird, Lynne M, Ceulemans, Sophia, Bebin, Martina, Bowling, Kevin M, Hiatt, Susan M, Lose, Edward J, Primiano, Michelle, Chung, Wendy K, Juusola, Jane, Akdemir, Zeynep C, Bainbridge, Matthew, Charng, Wu-Lin, Drummond-Borg, Margaret, Eldomery, Mohammad K, El-Hattab, Ayman W, Saleh, Mohammed AM, Bézieau, Stéphane, Cogné, Benjamin, Isidor, Bertrand, Küry, Sébastien, Lupski, James R, Myers, Richard M, Cooper, Gregory M, and Kutsche, Kerstin
- Subjects
Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Human Genome ,Biotechnology ,Brain Disorders ,Intellectual and Developmental Disabilities (IDD) ,Pediatric ,2.1 Biological and endogenous factors ,Aetiology ,Generic health relevance ,Adolescent ,Adult ,Amino Acid Substitution ,Ataxia ,Child ,Child ,Preschool ,Chromatin ,Cyclin-Dependent Kinase Inhibitor p21 ,Developmental Disabilities ,Exome ,Face ,Female ,Gene Expression Regulation ,Genes ,Reporter ,HEK293 Cells ,Humans ,Intellectual Disability ,Language Development Disorders ,Male ,Models ,Molecular ,Mosaicism ,Mutation ,Neurodevelopmental Disorders ,Protein Transport ,Syndrome ,Transcription Factors ,Transcription ,Genetic ,EBF3 ,de novo mutation ,developmental delay ,gene regulation ,intellectual disability ,transcription factor ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in ∼0.1% of individuals with unexplained neurodevelopmental disorders.
- Published
- 2017
28. Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis
- Author
-
Mohassel, Payam, Donkervoort, Sandra, Lone, Museer A., Nalls, Matthew, Gable, Kenneth, Gupta, Sita D., Foley, A. Reghan, Hu, Ying, Saute, Jonas Alex Morales, Moreira, Ana Lucila, Kok, Fernando, Introna, Alessandro, Logroscino, Giancarlo, Grunseich, Christopher, Nickolls, Alec R., Pourshafie, Naemeh, Neuhaus, Sarah B., Saade, Dimah, Gangfuß, Andrea, Kölbel, Heike, Piccus, Zoe, Le Pichon, Claire E., Fiorillo, Chiara, Ly, Cindy V., Töpf, Ana, Brady, Lauren, Specht, Sabine, Zidell, Aliza, Pedro, Helio, Mittelmann, Eric, Thomas, Florian P., Chao, Katherine R., Konersman, Chamindra G., Cho, Megan T., Brandt, Tracy, Straub, Volker, Connolly, Anne M., Schara, Ulrike, Roos, Andreas, Tarnopolsky, Mark, Höke, Ahmet, Brown, Robert H., Lee, Chia-Hsueh, Hornemann, Thorsten, Dunn, Teresa M., and Bönnemann, Carsten G.
- Published
- 2021
- Full Text
- View/download PDF
29. Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia
- Author
-
Muir, Alison M., Gardner, Jennifer F., van Jaarsveld, Richard H., de Lange, Iris M., van der Smagt, Jasper J., Wilson, Golder N., Dubbs, Holly, Goldberg, Ethan M., Zitano, Lia, Bupp, Caleb, Martinez, Jose, Srour, Myriam, Accogli, Andrea, Alhakeem, Afnan, Meltzer, Meira, Gropman, Andrea, Brewer, Carole, Caswell, Richard C., Montgomery, Tara, McKenna, Caoimhe, McKee, Shane, Powell, Corinna, Vasudevan, Pradeep C., Brady, Angela F., Joss, Shelagh, Tysoe, Carolyn, Noh, Grace, Tarnopolsky, Mark, Brady, Lauren, Zafar, Muhammad, Schrier Vergano, Samantha A., Murray, Brianna, Sawyer, Lindsey, Hainline, Bryan E., Sapp, Katherine, DeMarzo, Danielle, Huismann, Darcy J., Wentzensen, Ingrid M., Schnur, Rhonda E., Monaghan, Kristin G., Juusola, Jane, Rhodes, Lindsay, Dobyns, William B., Lecoquierre, Francois, Goldenberg, Alice, Polster, Tilman, Axer-Schaefer, Susanne, Platzer, Konrad, Klöckner, Chiara, Hoffman, Trevor L., MacArthur, Daniel G., O’Leary, Melanie C., VanNoy, Grace E., England, Eleina, Varghese, Vinod C., and Mefford, Heather C.
- Published
- 2021
- Full Text
- View/download PDF
30. A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental anomalies and epilepsy
- Author
-
Ni, Min, Afroze, Bushra, Xing, Chao, Pan, Chunxiao, Shao, Yanqiu, Cai, Ling, Cantarel, Brandi L., Pei, Jimin, Grishin, Nick V., Hewson, Stacy, Knight, Devon, Mahida, Sonal, Michel, Donnice, Tarnopolsky, Mark, Poduri, Annapurna, Rotenberg, Alexander, Sondheimer, Neal, and DeBerardinis, Ralph J.
- Published
- 2021
- Full Text
- View/download PDF
31. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features
- Author
-
Li, Dong, Wang, Qin, Bayat, Allan, Battig, Mark R., Zhou, Yijing, Bosch, Daniëlle G.M., van Haaften, Gijs, Granger, Leslie, Petersen, Andrea K., Pérez-Jurado, Luis A., Aznar-Laín, Gemma, Aneja, Anushree, Hancarova, Miroslava, Bendova, Sarka, Schwarz, Martin, Pourova, Radka Kremlikova, Sedlacek, Zdenek, Keena, Beth A., March, Michael E., Hou, Cuiping, O’Connor, Nora, Bhoj, Elizabeth J., Harr, Margaret H., Lemire, Gabrielle, Boycott, Kym M., Towne, Meghan, Li, Megan, Tarnopolsky, Mark, Brady, Lauren, Parker, Michael J., Faghfoury, Hanna, Parsley, Lea Kristin, Agolini, Emanuele, Dentici, Maria Lisa, Novelli, Antonio, Wright, Meredith, Palmquist, Rachel, Lai, Khanh, Scala, Marcello, Striano, Pasquale, Iacomino, Michele, Zara, Federico, Cooper, Annina, Maarup, Timothy J., Byler, Melissa, Lebel, Robert Roger, Balci, Tugce B., Louie, Raymond, Lyons, Michael, Douglas, Jessica, Nowak, Catherine, Afenjar, Alexandra, Hoyer, Juliane, Keren, Boris, Maas, Saskia M., Motazacker, Mahdi M., Martinez-Agosto, Julian A., Rabani, Ahna M., McCormick, Elizabeth M., Falk, Marni J., Ruggiero, Sarah M., Helbig, Ingo, Møller, Rikke S., Tessarollo, Lino, Ardori, Francesco Tomassoni, Palko, Mary Ellen, Hsieh, Tzung Chien, Krawitz, Peter M., Ganapathi, Mythily, Gelb, Bruce D., Jobanputra, Vaidehi, Wilson, Ashley, Greally, John, Jacquemont, Sébastien, Jizi, Khadijé, Bruel, Ange Line, Quelin, Chloé, Misra, Vinod K., Chick, Erika, Romano, Corrado, Greco, Donatella, Arena, Alessia, Morleo, Manuela, Nigro, Vincenzo, Seyama, Rie, Uchiyama, Yuri, Matsumoto, Naomichi, Taira, Ryoji, Tashiro, Katsuya, Sakai, Yasunari, Yigit, Gökhan, Wollnik, Bernd, Wagner, Michael, Kutsche, Barbara, Hurst, Anna C.E., Thompson, Michelle L., Schmidt, Ryan, Randolph, Linda, Spillmann, Rebecca C., Shashi, Vandana, Higginbotham, Edward J., Cordeiro, Dawn, Carnevale, Amanda, Costain, Gregory, Khan, Tayyaba, Funalot, Benoît, Mau-Them, Frederic Tran, Garcia Moya, Luis Fernandez, García-Miñaúr, Sixto, Osmond, Matthew, Chad, Lauren, Quercia, Nada, Carrasco, Diana, Li, Chumei, Sanchez-Valle, Amarilis, Kelley, Meghan, Nizon, Mathilde, Jensson, Brynjar O., Sulem, Patrick, Stefansson, Kari, Gorokhova, Svetlana, Busa, Tiffany, Rio, Marlène, Habdallah, Hamza Hadj, Lesieur-Sebellin, Marion, Amiel, Jeanne, Pingault, Véronique, Mercier, Sandra, Vincent, Marie, Philippe, Christophe, Fatus-Fauconnier, Clemence, Friend, Kathryn, Halligan, Rebecca K., Biswas, Sunita, Rosser, Jane, Shoubridge, Cheryl, Corbett, Mark, Barnett, Christopher, Gecz, Jozef, Leppig, Kathleen, Slavotinek, Anne, Marcelis, Carlo, Pfundt, Rolph, de Vries, Bert B.A., van Slegtenhorst, Marjon A., Brooks, Alice S., Cogne, Benjamin, Rambaud, Thomas, Tümer, Zeynep, Zackai, Elaine H., Akizu, Naiara, Song, Yuanquan, Hakonarson, Hakon, Li, Dong, Wang, Qin, Bayat, Allan, Battig, Mark R., Zhou, Yijing, Bosch, Daniëlle G.M., van Haaften, Gijs, Granger, Leslie, Petersen, Andrea K., Pérez-Jurado, Luis A., Aznar-Laín, Gemma, Aneja, Anushree, Hancarova, Miroslava, Bendova, Sarka, Schwarz, Martin, Pourova, Radka Kremlikova, Sedlacek, Zdenek, Keena, Beth A., March, Michael E., Hou, Cuiping, O’Connor, Nora, Bhoj, Elizabeth J., Harr, Margaret H., Lemire, Gabrielle, Boycott, Kym M., Towne, Meghan, Li, Megan, Tarnopolsky, Mark, Brady, Lauren, Parker, Michael J., Faghfoury, Hanna, Parsley, Lea Kristin, Agolini, Emanuele, Dentici, Maria Lisa, Novelli, Antonio, Wright, Meredith, Palmquist, Rachel, Lai, Khanh, Scala, Marcello, Striano, Pasquale, Iacomino, Michele, Zara, Federico, Cooper, Annina, Maarup, Timothy J., Byler, Melissa, Lebel, Robert Roger, Balci, Tugce B., Louie, Raymond, Lyons, Michael, Douglas, Jessica, Nowak, Catherine, Afenjar, Alexandra, Hoyer, Juliane, Keren, Boris, Maas, Saskia M., Motazacker, Mahdi M., Martinez-Agosto, Julian A., Rabani, Ahna M., McCormick, Elizabeth M., Falk, Marni J., Ruggiero, Sarah M., Helbig, Ingo, Møller, Rikke S., Tessarollo, Lino, Ardori, Francesco Tomassoni, Palko, Mary Ellen, Hsieh, Tzung Chien, Krawitz, Peter M., Ganapathi, Mythily, Gelb, Bruce D., Jobanputra, Vaidehi, Wilson, Ashley, Greally, John, Jacquemont, Sébastien, Jizi, Khadijé, Bruel, Ange Line, Quelin, Chloé, Misra, Vinod K., Chick, Erika, Romano, Corrado, Greco, Donatella, Arena, Alessia, Morleo, Manuela, Nigro, Vincenzo, Seyama, Rie, Uchiyama, Yuri, Matsumoto, Naomichi, Taira, Ryoji, Tashiro, Katsuya, Sakai, Yasunari, Yigit, Gökhan, Wollnik, Bernd, Wagner, Michael, Kutsche, Barbara, Hurst, Anna C.E., Thompson, Michelle L., Schmidt, Ryan, Randolph, Linda, Spillmann, Rebecca C., Shashi, Vandana, Higginbotham, Edward J., Cordeiro, Dawn, Carnevale, Amanda, Costain, Gregory, Khan, Tayyaba, Funalot, Benoît, Mau-Them, Frederic Tran, Garcia Moya, Luis Fernandez, García-Miñaúr, Sixto, Osmond, Matthew, Chad, Lauren, Quercia, Nada, Carrasco, Diana, Li, Chumei, Sanchez-Valle, Amarilis, Kelley, Meghan, Nizon, Mathilde, Jensson, Brynjar O., Sulem, Patrick, Stefansson, Kari, Gorokhova, Svetlana, Busa, Tiffany, Rio, Marlène, Habdallah, Hamza Hadj, Lesieur-Sebellin, Marion, Amiel, Jeanne, Pingault, Véronique, Mercier, Sandra, Vincent, Marie, Philippe, Christophe, Fatus-Fauconnier, Clemence, Friend, Kathryn, Halligan, Rebecca K., Biswas, Sunita, Rosser, Jane, Shoubridge, Cheryl, Corbett, Mark, Barnett, Christopher, Gecz, Jozef, Leppig, Kathleen, Slavotinek, Anne, Marcelis, Carlo, Pfundt, Rolph, de Vries, Bert B.A., van Slegtenhorst, Marjon A., Brooks, Alice S., Cogne, Benjamin, Rambaud, Thomas, Tümer, Zeynep, Zackai, Elaine H., Akizu, Naiara, Song, Yuanquan, and Hakonarson, Hakon
- Abstract
Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
- Published
- 2024
32. Next generation sequencing reveals novel compound heterozygous deletions in NDUFAF2 in a child with mitochondrial complex I deficiency, nuclear type 10.
- Author
-
Marshall, Aren E., Brady, Lauren, Yeh, Ed, Mears, Alan J., Lacaria, Melanie, Chakraborty, Pranesh, Tarnopolsky, Mark A., and Kernohan, Kristin D.
- Published
- 2024
- Full Text
- View/download PDF
33. Investigating the effects of dopamine on short‐ and long‐latency afferent inhibition.
- Author
-
Foglia, Stevie D., Adams, Faith C., Ramdeo, Karishma R., Drapeau, Chloe C., Turco, Claudia V., Tarnopolsky, Mark, Ma, Jinhui, and Nelson, Aimee J.
- Subjects
DOPAMINE ,TRANSCRANIAL magnetic stimulation ,PARKINSON'S disease ,NEURODEGENERATION ,PHARMACOLOGY - Abstract
Short‐ and long‐latency afferent inhibition (SAI and LAI respectively) are phenomenon whereby the motor evoked potential induced by transcranial magnetic stimulation (TMS) is inhibited by a sensory afferent volley consequent to nerve stimulation. It remains unclear whether dopamine participates in the genesis or modulation of SAI and LAI. The present study aimed to determine if SAI and LAI are modulated by levodopa (l‐DOPA). In this placebo‐controlled, double‐anonymized study Apo‐Levocarb (100 mg l‐DOPA in combination with 25 mg carbidopa) and a placebo were administered to 32 adult males (mean age 24 ± 3 years) in two separate sessions. SAI and LAI were evoked by stimulating the median nerve and delivering single‐pulse TMS over the motor hotspot corresponding to the first dorsal interosseous muscle of the right hand. SAI and LAI were quantified before and 1 h following ingestion of drug or placebo corresponding to the peak plasma concentration of Apo‐Levocarb. The results indicate that Apo‐Levocarb increases SAI and does not significantly alter LAI. These findings support literature demonstrating increased SAI following exogenous dopamine administration in neurodegenerative disorders. Key points: Short‐ and long‐latency afferent inhibition (SAI and LAI respectively) are measures of corticospinal excitability evoked using transcranial magnetic stimulation.SAI and LAI are reduced in conditions such as Parkinson's disease which suggests dopamine may be involved in the mechanism of afferent inhibition.125 mg of Apo‐Levocarb (100 mg dopamine) increases SAI but not LAI.This study increases our understanding of the pharmacological mechanism of SAI and LAI. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
34. Increased intra-mitochondrial lipofuscin aggregates with spherical dense body formation in mitochondrial myopathy
- Author
-
Lu, Jian-Qiang, Monaco, Cynthia M.F., Hawke, Thomas J., Yan, Chuanzhu, and Tarnopolsky, Mark A.
- Published
- 2020
- Full Text
- View/download PDF
35. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features
- Author
-
Li, Dong, primary, Wang, Qin, additional, Bayat, Allan, additional, Battig, Mark R., additional, Zhou, Yijing, additional, Bosch, Daniëlle G.M., additional, van Haaften, Gijs, additional, Granger, Leslie, additional, Petersen, Andrea K., additional, Pérez-Jurado, Luis A., additional, Aznar-Laín, Gemma, additional, Aneja, Anushree, additional, Hancarova, Miroslava, additional, Bendova, Sarka, additional, Schwarz, Martin, additional, Kremlíková Pourová, Radka, additional, Sedlacek, Zdenek, additional, Keena, Beth A., additional, March, Michael E., additional, Hou, Cuiping, additional, O'Connor, Nora, additional, Bhoj, Elizabeth J., additional, Harr, Margaret H., additional, Lemire, Gabrielle, additional, Boycott, Kym M., additional, Towne, Meghan C., additional, Li, Megan, additional, Tarnopolsky, Mark, additional, Brady, Lauren, additional, Parker, Michael J., additional, Faghfoury, Hanna, additional, Parsley, Lea Kristin, additional, Agolini, Emanuele, additional, Dentici, Maria Lisa, additional, Novelli, Antonio, additional, Wright, Meredith S., additional, Palmquist, Rachel, additional, Lai, Khanh, additional, Scala, Marcello, additional, Striano, Pasquale, additional, Iacomino, Michele, additional, Zara, Federico, additional, Cooper, Annina, additional, Maarup, Timothy J., additional, Byler, Melissa, additional, Lebel, Robert Roger, additional, Balci, Tugce B., additional, Louie, Raymond J., additional, Lyons, Michael J., additional, Douglas, Jessica, additional, Nowak, Catherine B., additional, Afenjar, Alexandra, additional, Hoyer, Juliane, additional, Keren, Boris, additional, Maas, Saskia M., additional, Motazacker, Mahdi M., additional, Martinez-Agosto, Julian A., additional, Rabani, Ahna M., additional, McCormick, Elizabeth M., additional, Falk, Marni, additional, Ruggiero, Sarah M., additional, Helbig, Ingo, additional, Møller, Rikke S., additional, Tessarollo, Lino, additional, Tomassoni-Ardori, Francesco, additional, Palko, Mary Ellen, additional, Hsieh, Tzung-Chien, additional, Krawitz, Peter M., additional, Ganapathi, Mythily, additional, Gelb, Bruce D., additional, Jobanputra, Vaidehi, additional, Wilson, Ashley, additional, Greally, John, additional, Jacquemont, Sébastien, additional, Jizi, Khadijé, additional, Ange-Line, Bruel, additional, Quelin, Chloé, additional, Misra, Vinod K., additional, Chick, Erika, additional, Romano, Corrado, additional, Greco, Donatella, additional, Arena, Alessia, additional, Morleo, Manuela, additional, Nigro, Vincenzo, additional, Seyama, Rie, additional, Uchiyama, Yuri, additional, Matsumoto, Naomichi, additional, Taira, Ryoji, additional, Tashiro, Katsuya, additional, Sakai, Yasunari, additional, Yigit, Gökhan, additional, Wollnik, Bernd, additional, Wagner, Michael, additional, Kutsche, Barbara, additional, Hurst, Anna C.E., additional, Thompson, Michelle L., additional, Schmidt, Ryan J., additional, Randolph, Linda M., additional, Spillmann, Rebecca C., additional, Shashi, Vandana, additional, Higginbotham, Edward J., additional, Cordeiro, Dawn, additional, Carnevale, Amanda, additional, Costain, Gregory, additional, Khan, Tayyaba, additional, Funalot, Benoît, additional, Tran Mau-Them, Frederic, additional, Fernandez Garcia Moya, Luis, additional, García-Miñaúr, Sixto, additional, Osmond, Matthew, additional, Chad, Lauren, additional, Quercia, Nada, additional, Carrasco, Diana, additional, Li, Chumei, additional, Sanchez-Valle, Amarilis, additional, Kelley, Meghan, additional, Nizon, Mathilde, additional, Jensson, Brynjar O., additional, Sulem, Patrick, additional, Stefansson, Kari, additional, Gorokhova, Svetlana, additional, Busa, Tiffany, additional, Rio, Marlène, additional, Hadj Abdallah, Hamza, additional, Lesieur-Sebellin, Marion, additional, Amiel, Jeanne, additional, Pingault, Véronique, additional, Mercier, Sandra, additional, Vincent, Marie, additional, Philippe, Christophe, additional, Fatus-Fauconnier, Clemence, additional, Friend, Kathryn, additional, Halligan, Rebecca K., additional, Biswas, Sunita, additional, Rosser, Jane M.R., additional, Shoubridge, Cheryl, additional, Corbett, Mark A., additional, Barnett, Christopher, additional, Gecz, Jozef, additional, Leppig, Kathleen A., additional, Slavotinek, Anne, additional, Marcelis, Carlo, additional, Pfundt, Rolph, additional, de Vries, Bert B.A., additional, van Slegtenhorst, Marjon A., additional, Brooks, Alice S., additional, Cogne, Benjamin, additional, Rambaud, Thomas, additional, Tümer, Zeynep, additional, Zackai, Elaine H., additional, Akizu, Naiara, additional, Song, Yuanquan, additional, and Hakonarson, Hakon, additional
- Published
- 2023
- Full Text
- View/download PDF
36. POLRMT mutations impair mitochondrial transcription causing neurological disease
- Author
-
Oláhová, Monika, Peter, Bradley, Szilagyi, Zsolt, Diaz-Maldonado, Hector, Singh, Meenakshi, Sommerville, Ewen W., Blakely, Emma L., Collier, Jack J., Hoberg, Emily, Stránecký, Viktor, Hartmannová, Hana, Bleyer, Anthony J., McBride, Kim L., Bowden, Sasigarn A., Korandová, Zuzana, Pecinová, Alena, Ropers, Hans-Hilger, Kahrizi, Kimia, Najmabadi, Hossein, Tarnopolsky, Mark A., Brady, Lauren I., Weaver, K. Nicole, Prada, Carlos E., Õunap, Katrin, Wojcik, Monica H., Pajusalu, Sander, Syeda, Safoora B., Pais, Lynn, Estrella, Elicia A., Bruels, Christine C., Kunkel, Louis M., Kang, Peter B., Bonnen, Penelope E., Mráček, Tomáš, Kmoch, Stanislav, Gorman, Gráinne S., Falkenberg, Maria, Gustafsson, Claes M., and Taylor, Robert W.
- Published
- 2021
- Full Text
- View/download PDF
37. Retraction Note to: Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice
- Author
-
Safdar, Adeel, Khrapko, Konstantin, Flynn, James M., Saleem, Ayesha, De Lisio, Michael, Johnston, Adam P. W., Kratysberg, Yevgenya, Samjoo, Imtiaz A., Kitaoka, Yu, Ogborn, Daniel I., Little, Jonathan P., Raha, Sandeep, Parise, Gianni, Akhtar, Mahmood, Hettinga, Bart P., Rowe, Glenn C., Arany, Zoltan, Prolla, Tomas A., and Tarnopolsky, Mark A.
- Published
- 2021
- Full Text
- View/download PDF
38. Paraspinal muscle ladybird homeobox 1 (LBX1) in adolescent idiopathic scoliosis: a cross-sectional study
- Author
-
Jennings, William, Hou, Maggie, Perterson, Devin, Missiuna, Paul, Thabane, Lehana, Tarnopolsky, Mark, and Samaan, M. Constantine
- Published
- 2019
- Full Text
- View/download PDF
39. Neurodevelopmental and associated changes in a patient with Xp22.31 duplication
- Author
-
MacColl, Christine, Stein, Nina, Tarnopolsky, Mark, and Lu, Jian-Qiang
- Published
- 2020
- Full Text
- View/download PDF
40. Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double‐blind, pilot study
- Author
-
Burton, Barbara K, Berger, Kenneth I, Lewis, Gregory D, Tarnopolsky, Mark, Treadwell, Marsha, Mitchell, John J, Muschol, Nicole, Jones, Simon A, Sutton, V Reid, Pastores, Gregory M, Lau, Heather, Sparkes, Rebecca, Genter, Fred, Shaywitz, Adam J, and Harmatz, Paul
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Clinical Sciences ,Clinical Trials and Supportive Activities ,Pain Research ,Chronic Pain ,Cardiovascular ,Clinical Research ,Evaluation of treatments and therapeutic interventions ,6.7 Physical ,6.1 Pharmaceuticals ,Musculoskeletal ,Adolescent ,Adult ,Child ,Chondroitinsulfatases ,Double-Blind Method ,Drug Administration Schedule ,Enzyme Replacement Therapy ,Exercise Test ,Female ,Heart Function Tests ,Humans ,Keratan Sulfate ,Male ,Mucopolysaccharidosis IV ,Muscle Strength ,Patient Safety ,Pilot Projects ,Recombinant Proteins ,Respiratory Function Tests ,Treatment Outcome ,Walking ,mucopolysaccharidosis IV ,cardiopulmonary exercise test ,safety ,respiratory function tests ,muscle strength ,physical endurance ,GALNS protein ,human [supplementary concept] ,enzyme replacement therapy ,Genetics ,Clinical sciences - Abstract
The primary treatment outcomes of a phase 2, randomized, double-blind, pilot study evaluating safety, physiological, and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome are herewith presented. Patients aged ≥7 years and able to walk ≥200 m in the 6-min walk test (6MWT) were randomized to elosulfase alfa 2.0 or 4.0 mg/kg/week for 27 weeks. The primary objective was to evaluate the safety of both doses. Secondary objectives were to evaluate effects on endurance (6MWT and 3-min stair climb test [3MSCT]), exercise capacity (cardio-pulmonary exercise test [CPET]), respiratory function, muscle strength, cardiac function, pain, and urine keratan sulfate (uKS) levels, and to determine pharmacokinetic parameters. Twenty-five patients were enrolled (15 randomized to 2.0 mg/kg/week and 10 to 4.0 mg/kg/week). No new or unexpected safety signals were observed. After 24 weeks, there were no improvements versus baseline in the 6MWT, yet numerical improvements were seen in the 3MSCT with 4.0 mg/kg/week. uKS and pharmacokinetic data suggested no linear relationship over the 2.0-4.0 mg/kg dose range. Overall, an abnormal exercise capacity (evaluated in 10 and 5 patients in the 2.0 and 4.0 mg/kg/week groups, respectively), impaired muscle strength, and considerable pain were observed at baseline, and there were trends towards improvements in all domains after treatment. In conclusion, preliminary data of this small study in a Morquio A population with relatively good endurance confirmed the acceptable safety profile of elosulfase alfa and showed a trend of increased exercise capacity and muscle strength and decreased pain.
- Published
- 2015
41. Cardiopulmonary Exercise Testing Reflects Improved Exercise Capacity in Response to Treatment in Morquio A Patients: Results of a 52-Week Pilot Study of Two Different Doses of Elosulfase Alfa
- Author
-
Berger, Kenneth I., Burton, Barbara K., Lewis, Gregory D., Tarnopolsky, Mark, Harmatz, Paul R., Mitchell, John J., Muschol, Nicole, Jones, Simon A., Sutton, V. Reid, Pastores, Gregory M., Lau, Heather, Sparkes, Rebecca, Shaywitz, Adam J., Baumgartner, Matthias, Series Editor, Patterson, Marc, Series Editor, Rahman, Shamima, Series Editor, Peters, Verena, Series Editor, Morava, Eva, Editor-in-Chief, and Zschocke, Johannes, Series Editor
- Published
- 2018
- Full Text
- View/download PDF
42. Novel caffeine derivatives mitigate hyperlipidemia by reducing PCSK9 expression and secretion
- Author
-
Stouth, Derek, Magolan, Jakob, Pare, Guillaume, Tarnopolsky, Mark, Macdonald, Melissa, Sguazzin, Matthew, and Austin, Richard
- Published
- 2024
- Full Text
- View/download PDF
43. Aerobic exercise elicits clinical adaptations in myotonic dystrophy type 1 patients independently of pathophysiological changes
- Author
-
Mikhail, Andrew I., Nagy, Peter L., Manta, Katherine, Rouse, Nicholas, Manta, Alexander, Ng, Sean Y., Nagy, Michael F., Smith, Paul, Lu, Jian-Qiang, Nederveen, Joshua P., Ljubicic, Vladimir, and Tarnopolsky, Mark A.
- Subjects
Aerobic exercises -- Health aspects ,Myotonic dystrophy -- Care and treatment -- Development and progression -- Genetic aspects ,Cycling -- Health aspects ,Health care industry - Abstract
BACKGROUND. Myotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardiorespiratory defects. Exercised DM1 mice exhibit numerous physiological benefits that are underpinned by reduced CUG foci and improved alternative splicing. However, the efficacy of physical activity in patients is unknown. METHODS. Eleven genetically diagnosed DM1 patients were recruited to examine the extent to which 12 weeks of cycling can recuperate clinical and physiological metrics. Furthermore, we studied the underlying molecular mechanisms through which exercise elicits benefits in skeletal muscle of DM1 patients. RESULTS. DM1 was associated with impaired muscle function, fitness, and lung capacity. Cycling evoked several clinical, physical, and metabolic advantages in DM1 patients. We highlight that exercise- induced molecular and cellular alterations in patients do not conform with previously published data in murine models and propose a significant role of mitochondrial function in DM1 pathology. Finally, we discovered a subset of small nucleolar RNAs (snoRNAs) that correlated to indicators of disease severity. CONCLUSION. With no available cures, our data support the efficacy of exercise as a primary intervention to partially mitigate the clinical progression of DM1. Additionally, we provide evidence for the involvement of snoRNAs and other noncoding RNAs in DM1 pathophysiology. TRIAL REGISTRATION. This trial was approved by the HiREB committee (no. 7901) and registered under ClinicalTrials.gov (NCT04187482). FUNDING. Neil and Leanne Petroff. Canadian Institutes of Health Research Foundation (no. 143325)., Introduction Myotonic dystrophy type 1 (DM1) is the most commonly diagnosed muscular dystrophy among adults and the second most prevalent of all muscular dystrophies (1). It is a progressive neuromuscular [...]
- Published
- 2022
- Full Text
- View/download PDF
44. Genome-wide DNA methylation changes with age in disease-free human skeletal muscle.
- Author
-
Zykovich, Artem, Hubbard, Alan, Flynn, James, Tarnopolsky, Mark, Fraga, Mario, Kerksick, Chad, Ogborn, Dan, MacNeil, Lauren, Mooney, Sean, and Melov, Simon
- Subjects
DNA methylation ,epigenome ,genomics ,human aging ,postmitotic ,skeletal muscle ,Adolescent ,Adult ,Aged ,Aging ,Base Composition ,CpG Islands ,DNA Methylation ,Gene Expression Regulation ,Gene Ontology ,Genome ,Human ,Humans ,Male ,Muscle ,Skeletal ,Signal Transduction ,Young Adult - Abstract
A decline in skeletal muscle mass and function with aging is well recognized, but remains poorly characterized at the molecular level. Here, we report for the first time a genome-wide study of DNA methylation dynamics in skeletal muscle of healthy male individuals during normal human aging. We predominantly observed hypermethylation throughout the genome within the aged group as compared to the young subjects. Differentially methylated CpG (dmCpG) nucleotides tend to arise intragenically and are underrepresented in promoters and are overrepresented in the middle and 3 end of genes. The intragenic methylation changes are overrepresented in genes that guide the formation of the junction of the motor neuron and myofibers. We report a low level of correlation of gene expression from previous studies of aged muscle with our current analysis of DNA methylation status. For those genes that had both changes in methylation and gene expression with age, we observed a reverse correlation, with the exception of intragenic hypermethylated genes that were correlated with an increased gene expression. We suggest that a minimal number of dmCpG sites or select sites are required to be altered in order to correlate with gene expression changes. Finally, we identified 500 dmCpG sites that perform well in discriminating young from old samples. Our findings highlight epigenetic links between aging postmitotic skeletal muscle and DNA methylation.
- Published
- 2014
45. Menstrual cycle hormones and oral contraceptives: A multi-method systems physiology-based review of their impact on key aspects of female physiology
- Author
-
D'Souza, Alysha C., primary, Wageh, Mai, additional, Williams, Jennifer S., additional, Colenso-Semple, Lauren M., additional, McCarthy, Devin G., additional, Mckay, Alannah K.A., additional, Elliott-Sale, Kirsty J., additional, Burke, Louise M., additional, Parise, Gianni, additional, MacDonald, Maureen J., additional, Tarnopolsky, Mark A., additional, and Phillips, Stuart M., additional
- Published
- 2023
- Full Text
- View/download PDF
46. Pediatric Peroneal Nerve Palsy Secondary to Fibular Osteochondroma
- Author
-
Leveille, Cameron F., primary, Zhu, Xi Ming, additional, Chen, Jeffrey, additional, Burrow, Sarah R., additional, Wang, Yongdong, additional, Tarnopolsky, Mark, additional, and Barkho, Jouseph O., additional
- Published
- 2023
- Full Text
- View/download PDF
47. Skeletal Muscle Mitochondrial Morphology Negatively Affected by Loss of Xin
- Author
-
Martin, Grace, primary, Al-Sajee, Dhuha, additional, Gingrich, Molly, additional, Chattha, Rimsha, additional, Akcan, Michael, additional, Monaco, Cynthia MF, additional, Hughes, Meghan C, additional, Perry, Christopher GR, additional, Rebalka, Irena A, additional, Tarnopolsky, Mark A, additional, and Hawke, Thomas J, additional
- Published
- 2023
- Full Text
- View/download PDF
48. Case report: A case of spinal muscular atrophy in a preterm infant: risks and benefits of treatment
- Author
-
Nigro, Elisa, primary, Grunebaum, Eyal, additional, Kamath, Binita, additional, Licht, Christoph, additional, Malcolmson, Caroline, additional, Jeewa, Aamir, additional, Campbell, Craig, additional, McMillan, Hugh, additional, Chakraborty, Pranesh, additional, Tarnopolsky, Mark, additional, and Gonorazky, Hernan, additional
- Published
- 2023
- Full Text
- View/download PDF
49. Novel Multi-Ingredient Supplement Facilitates Weight Loss and Improves Body Composition in Overweight and Obese Individuals: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial
- Author
-
Nederveen, Joshua P., primary, Mastrolonardo, Alexander J., additional, Xhuti, Donald, additional, Di Carlo, Alessia, additional, Manta, Katherine, additional, Fuda, Matthew R., additional, and Tarnopolsky, Mark A., additional
- Published
- 2023
- Full Text
- View/download PDF
50. Gender Differences in Metabolism
- Author
-
Tarnopolsky, Mark, primary
- Published
- 2020
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.