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4 results on '"Keagle, Pamela"'

1. Systematic rare variant analyses identify RAB32as a susceptibility gene for familial Parkinson’s disease

Author

Hop, Paul J., Lai, Dongbing, Keagle, Pamela J., Baron, Desiree M., Kenna, Brendan J., Kooyman, Maarten, Shankaracharya, Halter, Cheryl, Straniero, Letizia, Asselta, Rosanna, Bonvegna, Salvatore, Soto-Beasley, Alexandra I., Wszolek, Zbigniew K., Uitti, Ryan J., Isaias, Ioannis Ugo, Pezzoli, Gianni, Ticozzi, Nicola, Ross, Owen A., Veldink, Jan H., Foroud, Tatiana M., Kenna, Kevin P., and Landers, John E.

Abstract

Despite substantial progress, causal variants are identified only for a minority of familial Parkinson’s disease (PD) cases, leaving high-risk pathogenic variants unidentified1,2. To identify such variants, we uniformly processed exome sequencing data of 2,184 index familial PD cases and 69,775 controls. Exome-wide analyses converged on RAB32as a novel PD gene identifying c.213C > G/p.S71R as a high-risk variant presenting in ~0.7% of familial PD cases while observed in only 0.004% of controls (odds ratio of 65.5). This variant was confirmed in all cases via Sanger sequencing and segregated with PD in three families. RAB32encodes a small GTPase known to interact with LRRK2 (refs. 3,4). Functional analyses showed that RAB32 S71R increases LRRK2 kinase activity, as indicated by increased autophosphorylation of LRRK2 S1292. Here our results implicate mutant RAB32 in a key pathological mechanism in PD—LRRK2 kinase activity5–7—and thus provide novel insights into the mechanistic connections between RAB family biology, LRRK2 and PD risk.

Published
2024
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2. Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Author

Johnson, Janel O., Chia, Ruth, Miller, Danny E., Li, Rachel, Kumaran, Ravindran, Abramzon, Yevgeniya, Alahmady, Nada, Renton, Alan E., Topp, Simon D., Gibbs, J. Raphael, Cookson, Mark R., Sabir, Marya S., Dalgard, Clifton L., Troakes, Claire, Jones, Ashley R., Shatunov, Aleksey, Iacoangeli, Alfredo, Al Khleifat, Ahmad, Ticozzi, Nicola, Silani, Vincenzo, Gellera, Cinzia, Blair, Ian P., Dobson-Stone, Carol, Kwok, John B., Bonkowski, Emily S., Palvadeau, Robin, Tienari, Pentti J., Morrison, Karen E., Shaw, Pamela J., Al-Chalabi, Ammar, Brown, Robert H., Calvo, Andrea, Mora, Gabriele, Al-Saif, Hind, Gotkine, Marc, Leigh, Fawn, Chang, Irene J., Perlman, Seth J., Glass, Ian, Scott, Anna I., Shaw, Christopher E., Basak, A. Nazli, Landers, John E., Chiò, Adriano, Crawford, Thomas O., Smith, Bradley N., Traynor, Bryan J., Smith, Bradley N., Ticozzi, Nicola, Fallini, Claudia, Gkazi, Athina Soragia, Topp, Simon D., Scotter, Emma L., Kenna, Kevin P., Keagle, Pamela, Tiloca, Cinzia, Vance, Caroline, Troakes, Claire, Colombrita, Claudia, King, Andrew, Pensato, Viviana, Castellotti, Barbara, Baas, Frank, ten Asbroek, Anneloor L. M. A., McKenna-Yasek, Diane, McLaughlin, Russell L., Polak, Meraida, Asress, Seneshaw, Esteban-Pérez, Jesús, Stevic, Zorica, D’Alfonso, Sandra, Mazzini, Letizia, Comi, Giacomo P., Del Bo, Roberto, Ceroni, Mauro, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, van Rheenen, Wouter, Rademakers, Rosa, van Blitterswijk, Marka, Lauria, Giuseppe, Duga, Stefano, Corti, Stefania, Cereda, Cristina, Corrado, Lucia, Sorarù, Gianni, Williams, Kelly L., Nicholson, Garth A., Blair, Ian P., Leblond-Manry, Claire, Rouleau, Guy A., Hardiman, Orla, Morrison, Karen E., Veldink, Jan H., van den Berg, Leonard H., Al-Chalabi, Ammar, Pall, Hardev, Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Taroni, Franco, García-Redondo, Alberto, Wu, Zheyang, Glass, Jonathan D., Gellera, Cinzia, Ratti, Antonia, Brown, Robert H., Silani, Vincenzo, Shaw, Christopher E., Landers, John E., Dalgard, Clifton L., Adeleye, Adelani, Soltis, Anthony R., Alba, Camille, Viollet, Coralie, Bacikova, Dagmar, Hupalo, Daniel N., Sukumar, Gauthaman, Pollard, Harvey B., Wilkerson, Matthew D., Martinez, Elisa McGrath, Abramzon, Yevgeniya, Ahmed, Sarah, Arepalli, Sampath, Baloh, Robert H., Bowser, Robert, Brady, Christopher B., Brice, Alexis, Broach, James, Campbell, Roy H., Camu, William, Chia, Ruth, Cooper-Knock, John, Ding, Jinhui, Drepper, Carsten, Drory, Vivian E., Dunckley, Travis L., Eicher, John D., England, Bryce K., Faghri, Faraz, Feldman, Eva, Floeter, Mary Kay, Fratta, Pietro, Geiger, Joshua T., Gerhard, Glenn, Gibbs, J. Raphael, Gibson, Summer B., Glass, Jonathan D., Hardy, John, Harms, Matthew B., Heiman-Patterson, Terry D., Hernandez, Dena G., Jansson, Lilja, Kirby, Janine, Kowall, Neil W., Laaksovirta, Hannu, Landeck, Natalie, Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J. L., Maragakis, Nicholas J., Mora, Gabriele, Mouzat, Kevin, Murphy, Natalie A., Myllykangas, Liisa, Nalls, Mike A., Orrell, Richard W., Ostrow, Lyle W., Pamphlett, Roger, Pickering-Brown, Stuart, Pioro, Erik P., Pletnikova, Olga, Pliner, Hannah A., Pulst, Stefan M., Ravits, John M., Renton, Alan E., Rivera, Alberto, Robberecht, Wim, Rogaeva, Ekaterina, Rollinson, Sara, Rothstein, Jeffrey D., Scholz, Sonja W., Sendtner, Michael, Shaw, Pamela J., Sidle, Katie C., Simmons, Zachary, Singleton, Andrew B., Smith, Nathan, Stone, David J., Tienari, Pentti J., Troncoso, Juan C., Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M., Van Den Bosch, Ludo, Zinman, Lorne, Landers, John E., Chiò, Adriano, Traynor, Bryan J., Angelocola, Stefania M., Ausiello, Francesco P., Barberis, Marco, Bartolomei, Ilaria, Battistini, Stefania, Bersano, Enrica, Bisogni, Giulia, Borghero, Giuseppe, Brunetti, Maura, Cabona, Corrado, Calvo, Andrea, Canale, Fabrizio, Canosa, Antonio, Cantisani, Teresa A., Capasso, Margherita, Caponnetto, Claudia, Cardinali, Patrizio, Carrera, Paola, Casale, Federico, Chiò, Adriano, Colletti, Tiziana, Conforti, Francesca L., Conte, Amelia, Conti, Elisa, Corbo, Massimo, Cuccu, Stefania, Dalla Bella, Eleonora, D’Errico, Eustachio, DeMarco, Giovanni, Dubbioso, Raffaele, Ferrarese, Carlo, Ferraro, Pilar M., Filippi, Massimo, Fini, Nicola, Floris, Gianluca, Fuda, Giuseppe, Gallone, Salvatore, Gianferrari, Giulia, Giannini, Fabio, Grassano, Maurizio, Greco, Lucia, Iazzolino, Barbara, Introna, Alessandro, La Bella, Vincenzo, Lattante, Serena, Lauria, Giuseppe, Liguori, Rocco, Logroscino, Giancarlo, Logullo, Francesco O., Lunetta, Christian, Mandich, Paola, Mandrioli, Jessica, Manera, Umberto, Manganelli, Fiore, Marangi, Giuseppe, Marinou, Kalliopi, Marrosu, Maria Giovanna, Martinelli, Ilaria, Messina, Sonia, Moglia, Cristina, Mora, Gabriele, Mosca, Lorena, Murru, Maria R., Origone, Paola, Passaniti, Carla, Petrelli, Cristina, Petrucci, Antonio, Pozzi, Susanna, Pugliatti, Maura, Quattrini, Angelo, Ricci, Claudia, Riolo, Giulia, Riva, Nilo, Russo, Massimo, Sabatelli, Mario, Salamone, Paolina, Salivetto, Marco, Salvi, Fabrizio, Santarelli, Marialuisa, Sbaiz, Luca, Sideri, Riccardo, Simone, Isabella, Simonini, Cecilia, Spataro, Rossella, Tanel, Raffaella, Tedeschi, Gioacchino, Ticca, Anna, Torriello, Antonella, Tranquilli, Stefania, Tremolizzo, Lucio, Trojsi, Francesca, Vasta, Rosario, Vacchiano, Veria, Vita, Giuseppe, Volanti, Paolo, Zollino, Marcella, and Zucchi, Elisabetta

Abstract

IMPORTANCE: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. OBJECTIVE: To identify the genetic variants associated with juvenile ALS. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. MAIN OUTCOMES AND MEASURES: De novo variants present only in the index case and not in unaffected family members. RESULTS: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. CONCLUSIONS AND RELEVANCE: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

Published
2021
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3. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Author

Kenna, Kevin P, van Doormaal, Perry T C, Dekker, Annelot M, Ticozzi, Nicola, Kenna, Brendan J, Diekstra, Frank P, van Rheenen, Wouter, van Eijk, Kristel R, Jones, Ashley R, Keagle, Pamela, Shatunov, Aleksey, Sproviero, William, Smith, Bradley N, van Es, Michael A, Topp, Simon D, Kenna, Aoife, Miller, Jack W, Fallini, Claudia, Tiloca, Cinzia, McLaughlin, Russell L, Vance, Caroline, Troakes, Claire, Colombrita, Claudia, Mora, Gabriele, Calvo, Andrea, Verde, Federico, Al-Sarraj, Safa, King, Andrew, Calini, Daniela, de Belleroche, Jacqueline, Baas, Frank, van der Kooi, Anneke J, de Visser, Marianne, ten Asbroek, Anneloor L M A, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Muñoz-Blanco, José Luis, Strom, Tim M, Meitinger, Thomas, Morrison, Karen E, Lauria, Giuseppe, Williams, Kelly L, Leigh, P Nigel, Nicholson, Garth A, Blair, Ian P, Leblond, Claire S, Dion, Patrick A, Rouleau, Guy A, Pall, Hardev, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Taroni, Franco, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Esteban-Pérez, Jesús, García-Redondo, Alberto, Van Damme, Phillip, Robberecht, Wim, Chio, Adriano, Gellera, Cinzia, Drepper, Carsten, Sendtner, Michael, Ratti, Antonia, Glass, Jonathan D, Mora, Jesús S, Basak, Nazli A, Hardiman, Orla, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Brown, Robert H, Al-Chalabi, Ammar, Silani, Vincenzo, Shaw, Christopher E, van den Berg, Leonard H, Veldink, Jan H, and Landers, John E

Abstract

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.

Published
2016
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4. ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function

Author

Baron, Desiree M., Fenton, Adam R., Saez-Atienzar, Sara, Giampetruzzi, Anthony, Sreeram, Aparna, Shankaracharya, Keagle, Pamela J., Doocy, Victoria R., Smith, Nathan J., Danielson, Eric W., Andresano, Megan, McCormack, Mary C., Garcia, Jaqueline, Bercier, Valérie, Van Den Bosch, Ludo, Brent, Jonathan R., Fallini, Claudia, Traynor, Bryan J., Holzbaur, Erika L.F., and Landers, John E.

Abstract

Understanding the pathogenic mechanisms of disease mutations is critical to advancing treatments. ALS-associated mutations in the gene encoding the microtubule motor KIF5A result in skipping of exon 27 (KIF5AΔExon27) and the encoding of a protein with a novel 39 amino acid residue C-terminal sequence. Here, we report that expression of ALS-linked mutant KIF5A results in dysregulated motor activity, cellular mislocalization, altered axonal transport, and decreased neuronal survival. Single-molecule analysis revealed that the altered C terminus of mutant KIF5A results in a constitutively active state. Furthermore, mutant KIF5A possesses altered protein and RNA interactions and its expression results in altered gene expression/splicing. Taken together, our data support the hypothesis that causative ALS mutations result in a toxic gain of function in the intracellular motor KIF5A that disrupts intracellular trafficking and neuronal homeostasis.

Published
2022
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