Found to cause complex HSP in 3 children
Studies in patient skin cells, human kidney cells and in fruit flies show that variants in the SPTSSA gene cause imbalance in lipid production and regulation, and are responsible for impaired early brain development and function.
Abstract
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 comprised 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 is 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 pathogenicity of the SPTSSA variants and point to excessive sphingolipid synthesis due to impaired homeostatic regulation of serine palmitoyltransferase as responsible for defects in early brain development and function.
SOURCE: Brain. 2023 Jan 30;awac460. doi: 10.1093/brain/awac460. Online ahead of print. PMID: 36718090 Published by Oxford University Press on behalf of the Guarantors of Brain 2023.
SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia
Siddharth Srivastava 1 , Hagar Mor Shaked 2 , Kenneth Gable 3 , Sita D Gupta 3 , Xueyang Pan 4 5 , Niranjanakumari Somashekarappa 3 , Gongshe Han 3 , Payam Mohassel 6 , Marc Gotkine 2 , Elizabeth Doney 7 , Paula Goldenberg 8 , Queenie K G Tan 9 , Yi Gong 10 11 , Benjamin Kleinstiver 11 12 13 , Brian Wishart 14 , Heidi Cope 9 , Claudia Brito Pires 10 11 , Hannah Stutzman 11 12 , Rebecca C Spillmann 9 ; Undiagnosed Disease Network; Reza Sadjadi 10 , Orly Elpeleg 2 , Chia-Hsueh Lee 15 , Hugo J Bellen 4 5 , Simon Edvardson 16 , Florian Eichler 10 11 , Teresa M Dunn 3
Undiagnosed Disease Network: Mercedes E Alejandro, Mahshid S Azamian, Carlos A Bacino, Ashok Balasubramanyam, Lindsay C Burrage, Hsiao-Tuan Chao, Gary D Clark, William J Craigen, Hongzheng Dai, Shweta U Dhar, Lisa T Emrick, Alica M Goldman, Neil A Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R Lalani, Brendan H Lee, Richard A Lewis, Ronit Marom, Paolo M Moretti, David R Murdock, Sarah K Nicholas, James P Orengo, Jennifer E Posey, Lorraine Potocki, Jill A Rosenfeld, Susan L Samson, Daryl A Scott, Alyssa A Tran, Tiphanie P Vogel, Michael F Wangler, Shinya Yamamoto, Christine M Eng, Pengfei Liu, Patricia A Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline 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 Coggins, Cynthia M Cooper, Elizabeth L Fieg, Frances 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 M Stoler, David A Sweetser, Melissa Walker, Chris A Walsh, Cecilia Esteves, Emily G Kelley, Isaac S Kohane, Kimberly LeBlanc, Alexa T McCray, Anna Nagy, Surendra Dasari, Brendan C Lanpher, Ian R Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A Colley, Jyoti G Dayal, David J Eckstein, Laurie C Findley, Donna M Krasnewich, Laura A Mamounas, Teri A Manolio, John J 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 Ferreira, Rena A Godfrey, Catherine A Groden, Ellen F Macnamara, Valerie V Maduro, Thomas C Markello, Avi Nath, Donna Novacic, Barbara N Pusey, Camilo Toro, Colleen E Wahl, Eva Baker, Elizabeth A Burke, David R Adams, William A Gahl, May Christine V Malicdan, Cynthia J Tifft, Lynne A Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M Hisama, Martha Horike-Pyne, Gail P Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A Ashley, Gill Bejerano, Jonathan A Bernstein, Devon Bonner, Terra R Coakley, Liliana Fernandez, Paul G Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N Kohler, Elijah Kravets, Marta M Majcherska, Beth A Martin, Shruti Marwaha, Colleen E McCormack, Archana N Raja, Chloe M Reuter, Maura Ruzhnikov, Jacinda B Sampson, Kevin S Smith, Shirley 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, Martin G Martin, Julian 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 Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochi, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H Newman, John A PhillipsIII, Lynette Rives, Amy K Robertson, Emily Solem, Joy D Cogan, F Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel
1. Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
2. Department of Genetics, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
3. Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
5. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA.
6. Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.
7. Massachusetts Eye and Ear, Boston, MA 02114, USA.
8. Department of Pediatrics, Section on Medical Genetics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
9. Department of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, NC 27710, USA.
10. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
11. Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
12. Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
13. Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
14. Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA 02114, USA.
15. Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
16. Pediatric Neurology Unit, Hadassah University Hospital, Mount Scopus, Jerusalem 91240, Israel.