SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia

作者：Siddharth Srivastava, Hagar Mor Shaked, Kenneth S. Gable, Sita D. Gupta, Xueyang Pan, Niranjanakumari Somashekarappa, Gongshe Han, Payam Mohassel, Marc Gotkine, Elizabeth Doney, Paula C. Goldenberg, Queenie K.‐G. Tan, Yi Gong, Benjamin P. Kleinstiver, Brian D. Wishart, Heidi Cope, Cláudia Brito Pires, Hannah E. Stutzman, Rebecca C. Spillmann, Undiagnosed Disease Network, Mercedes E. Alejandro, Mahshid Sababi Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay Catherine Burrage, Hsiao‐Tuan Chao, Gary Clark, William James Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea P. Karaviti, Seema R. Lalani, Brendan Lee, Richard Alan Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah Kogan Nicholas, James Peter Orengo, Jennifer Ellen Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan Leanne Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward M. Behrens, Matthew A. Deardorff, Marni J. Falk, Kelly Hassey, Kathleen E. Sullivan, Adeline L. Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie‐Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K-G Tan, Nicole M Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew P. Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances A. High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A Rao, Lance H. Rodan, Edwin K. Silverman, Joan Marilyn Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nemes Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Éva Morava, Devin Oglesbee, Güney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Chang, Irman Forghani, Alana L. Grajewski, Rosario M. Isasi, Byron Lam, Roy C. Levitt, Xue Zhong Liu, Jacob L. McCauley, Ralph L. Sacco, Mario Saporta, Judy L. Schaechter, Mustafa Tekin, Fred Telischi, Willa L. Thorson, Stephan L. Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John Joseph Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos R. Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Braden Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva H. Baker, Elizabeth A. Burke, David R. Adams, William Allen Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Jeongseok Yang, Bradley M. Power, Bernadette Gochuico, Laryssa A. Huryn, Lea L. Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey E. Thurm, Wadih M. Zein, Muhammad Yousef, Margaret P Adam, Laura M. Amendola, Michael J. Bamshad, Anita E. Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna M. Boyd, Peter H. Byers, Sirisak Chanprasert, Michael L. Cunningham, Katrina M. Dipple, Daniel Doherty, Dawn Earl, Ian A. Glass, Katie L. Golden‐Grant, Sihoun Hahn, Anne V Hing, Fuki Marie Hisama, Martha J. Horike-Pyne, Gail Pairitz Jarvik, Jeffrey G. Jarvik, Suman Jayadev, Christina T. Lam, Kenneth R. Maravilla, Heather C. Mefford, Justin L. Merritt, Ghayda Mirzaa, Deborah A. Nickerson, Wendy H. Raskind, Natalie L. Rosenwasser, C Ron Scott, Angela Sun, Virginia P. Sybert, Stephanie E Wallace, Mark H. Wener, Tara Lynn Wenger, Euan Angus Ashley, Gill Bejerano, Jonathan Adam Bernstein, Devon E. Bonner, Terra R. Coakley, Liliana Fernández, Paul Graham Fisher, Laure Frésard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana Natarajan Raja, Chloe M. Reuter, Maura R. Z. Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley C. Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano‐Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martín G. Martín, Julián A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves‐Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin C. Alvey, Ashley Andrews, Jim Bale, John Peyton Bohnsack, Lorenzo D. Botto, John C. Carey, Laura Pace, Nicola Longo, Gábor Marth, Paolo M. Moretti, Aaron R. Quinlan, Matt Velinder, Dave Viskochi, Pınar Bayrak‐Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, J. Phillip Kennedy, Mary Kozuira, John H. Newman, John A PhillipsIII, Lynette C. Rives, Amy K. Robertson, Emily P. Solem, Joy D Cogan, Francis Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica‐Krezel, Reza Sadjadi, Orly N Elpeleg, Chia‐Hsueh Lee, Hugo Jozef Bellen, Simon Edvardson, Florian Eichler, Teresa M. Dunn · 发表于：Brain · 年份：2022 · DOI：10.1093/brain/awac460 · 被引用次数：38 · 研究领域：Sphingolipid Metabolism and Signaling、Lysosomal Storage Disorders Research、Cellular transport and secretion

Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes. Serine palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA. Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated. Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive. Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting with a complex form of hereditary spastic paraplegia. The effect of these variants on the catalytic activity and homeostatic regulation of serine palmitoyltransferase was investigated in human embryonic kidney cells, patient fibroblasts and Drosophila. Our results showed that two different pathogenic variants in SPTSSA caused a hereditary spastic paraplegia resulting in progressive motor disturbance with variable sensorineural hearing loss and language/cognitive dysfunction in three individuals. The variants in SPTSSA impaired the negative regulation of serine palmitoyltransferase by ORMDLs leading to excessive sphingolipid synthesis based on biochemical studies and in vivo studies in Drosophila. These findings support the patho...