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

Siddharth Srivastava; Hagar Mor Shaked; Kenneth Gable; Sita D. Gupta; Xueyang Pan; Niranjanakumari Somashekarappa; Gongshe Han; Payam Mohassel; Marc Gotkine; Elizabeth Doney; Paula Goldenberg; Queenie K.G. Tan; Yi Gong; Benjamin Kleinstiver; Brian Wishart; Heidi Cope; Claudia Brito Pires; Hannah Stutzman; Rebecca C. Spillmann; 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; Reza Sadjadi; Orly Elpeleg; Chia Hsueh Lee; Hugo J. Bellen; Simon Edvardson; Florian Eichler; Teresa M. Dunn

doi:10.1093/brain/awac460

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

Siddharth Srivastava, Hagar Mor Shaked, Kenneth Gable, Sita D. Gupta, Xueyang Pan, Niranjanakumari Somashekarappa, Gongshe Han, Payam Mohassel, Marc Gotkine, Elizabeth Doney, Paula Goldenberg, Queenie K.G. Tan, Yi Gong, Benjamin Kleinstiver, Brian Wishart, Heidi Cope, Claudia Brito Pires, Hannah Stutzman, Rebecca C. Spillmann, Mercedes E. AlejandroMahshid 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, Reza Sadjadi, Orly Elpeleg, Chia Hsueh Lee, Hugo J. Bellen, Simon Edvardson, Florian Eichler, Teresa M. Dunn

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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 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 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.

Original language	English
Pages (from-to)	1420-1435
Number of pages	16
Journal	Brain
Volume	146
Issue number	4
DOIs	https://doi.org/10.1093/brain/awac460
State	Published - Apr 1 2023

Keywords

ORMDLs
SPTSSA
hereditary spastic paraplegia
serine palmitoyltransferase
sphingolipids

Access to Document

10.1093/brain/awac460

Cite this

Srivastava, S., Shaked, H. M., Gable, K., Gupta, S. D., Pan, X., Somashekarappa, N., Han, G., Mohassel, P., Gotkine, M., Doney, E., Goldenberg, P., Tan, Q. K. G., Gong, Y., Kleinstiver, B., Wishart, B., Cope, H., Pires, C. B., Stutzman, H., Spillmann, R. C., ... Dunn, T. M. (2023). SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia. Brain, 146(4), 1420-1435. https://doi.org/10.1093/brain/awac460

@article{5ad9b7043510463a83f4d65c28f90f86,

title = "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia",

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 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 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.",

keywords = "ORMDLs, SPTSSA, hereditary spastic paraplegia, serine palmitoyltransferase, sphingolipids",

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

note = "Publisher Copyright: {\textcopyright} 2023 Published by Oxford University Press on behalf of the Guarantors of Brain.",

year = "2023",

month = apr,

day = "1",

doi = "10.1093/brain/awac460",

language = "English",

volume = "146",

pages = "1420--1435",

journal = "Brain",

issn = "0006-8950",

number = "4",

}

Srivastava, S, Shaked, HM, Gable, K, Gupta, SD, Pan, X, Somashekarappa, N, Han, G, Mohassel, P, Gotkine, M, Doney, E, Goldenberg, P, Tan, QKG, Gong, Y, Kleinstiver, B, Wishart, B, Cope, H, Pires, CB, Stutzman, H, Spillmann, RC, Alejandro, ME, Azamian, MS, Bacino, CA, Balasubramanyam, A, Burrage, LC, Chao, HT, Clark, GD, Craigen, WJ, Dai, H, Dhar, SU, Emrick, LT, Goldman, AM, Hanchard, NA, Jamal, F, Karaviti, L, Lalani, SR, Lee, BH, Lewis, RA, Marom, R, Moretti, PM, Murdock, DR, Nicholas, SK, Orengo, JP, Posey, JE, Potocki, L, Rosenfeld, JA, Samson, SL, Scott, DA, Tran, AA, Vogel, TP, Wangler, MF, Yamamoto, S, Eng, CM, Liu, P, Ward, PA, Behrens, E, Deardorff, M, Falk, M, Hassey, K, Sullivan, K, Vanderver, A, Goldstein, DB, Cope, H, Mcconkie-Rosell, A, Schoch, K, Shashi, V, Smith, EC, Spillmann, RC, Sullivan, JA, Tan, QKG, Walley, NM, Agrawal, PB, Beggs, AH, Berry, GT, Briere, LC, Cobban, LA, Coggins, M, Cooper, CM, Fieg, EL, High, F, Holm, IA, Korrick, S, Krier, JB, Lincoln, SA, Loscalzo, J, Maas, RL, Macrae, CA, Pallais, JC, Rao, DA, Rodan, LH, Silverman, EK, Stoler, JM, Sweetser, DA, Walker, M, Walsh, CA, Esteves, C, Kelley, EG, Kohane, IS, Leblanc, K, Mccray, AT, Nagy, A, Dasari, S, Lanpher, BC, Lanza, IR, Morava, E, Oglesbee, D, Bademci, G, Barbouth, D, Bivona, S, Carrasquillo, O, Chang, TCP, Forghani, I, Grajewski, A, Isasi, R, Lam, B, Levitt, R, Liu, XZ, Mccauley, J, Sacco, R, Saporta, M, Schaechter, J, Tekin, M, Telischi, F, Thorson, W, Zuchner, S, Colley, HA, Dayal, JG, Eckstein, DJ, Findley, LC, Krasnewich, DM, Mamounas, LA, Manolio, TA, Mulvihill, JJ, Lamoure, GL, Goldrich, MP, Urv, TK, Doss, AL, Acosta, MT, Bonnenmann, C, D'souza, P, Draper, DD, Ferreira, C, Godfrey, RA, Groden, CA, Macnamara, EF, Maduro, VV, Markello, TC, Nath, A, Novacic, D, Pusey, BN, Toro, C, Wahl, CE, Baker, E, Burke, EA, Adams, DR, Gahl, WA, Malicdan, MCV, Tifft, CJ, Wolfe, LA, Yang, J, Power, B, Gochuico, B, Huryn, L, Latham, L, Davis, J, Mosbrook-Davis, D, Rossignol, F, Solomon, B, Macdowall, J, Thurm, A, Zein, W, Yousef, M, Adam, M, Amendola, L, Bamshad, M, Beck, A, Bennett, J, Berg-Rood, B, Blue, E, Boyd, B, Byers, P, Chanprasert, S, Cunningham, M, Dipple, K, Doherty, D, Earl, D, Glass, I, Golden-Grant, K, Hahn, S, Hing, A, Hisama, FM, Horike-Pyne, M, Jarvik, GP, Jarvik, J, Jayadev, S, Lam, C, Maravilla, K, Mefford, H, Merritt, JL, Mirzaa, G, Nickerson, D, Raskind, W, Rosenwasser, N, Scott, CR, Sun, A, Sybert, V, Wallace, S, Wener, M, Wenger, T, Ashley, EA, Bejerano, G, Bernstein, JA, Bonner, D, Coakley, TR, Fernandez, L, Fisher, PG, Fresard, L, Hom, J, Huang, Y, Kohler, JN, Kravets, E, Majcherska, MM, Martin, BA, Marwaha, S, Mccormack, CE, Raja, AN, Reuter, CM, Ruzhnikov, M, Sampson, JB, Smith, KS, Sutton, S, Tabor, HK, Tucker, BM, Wheeler, MT, Zastrow, DB, Zhao, C, Byrd, WE, Crouse, AB, Might, M, Nakano-Okuno, M, Whitlock, J, Brown, G, Butte, MJ, Dell'angelica, EC, Dorrani, N, Douine, ED, Fogel, BL, Gutierrez, I, Huang, A, Krakow, D, Lee, H, Loo, SK, Mak, BC, Martin, MG, Martínez-Agosto, JA, Mcgee, E, Nelson, SF, Nieves-Rodriguez, S, Palmer, CGS, Papp, JC, Parker, NH, Renteria, G, Signer, RH, Sinsheimer, JS, Wan, J, Wang, LK, Perry, KW, Woods, JD, Alvey, J, Andrews, A, Bale, J, Bohnsack, J, Botto, L, Carey, J, Pace, L, Longo, N, Marth, G, Moretti, P, Quinlan, A, Velinder, M, Viskochi, D, Bayrak-Toydemir, P, Mao, R, Westerfield, M, Bican, A, Brokamp, E, Duncan, L, Hamid, R, Kennedy, J, Kozuira, M, Newman, JH, Phillipsiii, JA, Rives, L, Robertson, AK, Solem, E, Cogan, JD, Cole, FS, Hayes, N, Kiley, D, Sisco, K, Wambach, J, Wegner, D, Baldridge, D , Pak, S , Schedl, T , Shin, J , Solnica-Krezel, L, Sadjadi, R, Elpeleg, O, Lee, CH, Bellen, HJ, Edvardson, S, Eichler, F & Dunn, TM 2023, 'SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia', Brain, vol. 146, no. 4, pp. 1420-1435. https://doi.org/10.1093/brain/awac460

TY - JOUR

T1 - SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia

AU - Srivastava, Siddharth

AU - Shaked, Hagar Mor

AU - Gable, Kenneth

AU - Gupta, Sita D.

AU - Pan, Xueyang

AU - Somashekarappa, Niranjanakumari

AU - Han, Gongshe

AU - Mohassel, Payam

AU - Gotkine, Marc

AU - Doney, Elizabeth

AU - Goldenberg, Paula

AU - Tan, Queenie K.G.

AU - Gong, Yi

AU - Kleinstiver, Benjamin

AU - Wishart, Brian

AU - Cope, Heidi

AU - Pires, Claudia Brito

AU - Stutzman, Hannah

AU - Spillmann, Rebecca C.

AU - Alejandro, Mercedes E.

AU - Azamian, Mahshid S.

AU - Bacino, Carlos A.

AU - Balasubramanyam, Ashok

AU - Burrage, Lindsay C.

AU - Chao, Hsiao Tuan

AU - Clark, Gary D.

AU - Craigen, William J.

AU - Dai, Hongzheng

AU - Dhar, Shweta U.

AU - Emrick, Lisa T.

AU - Goldman, Alica M.

AU - Hanchard, Neil A.

AU - Jamal, Fariha

AU - Karaviti, Lefkothea

AU - Lalani, Seema R.

AU - Lee, Brendan H.

AU - Lewis, Richard A.

AU - Marom, Ronit

AU - Moretti, Paolo M.

AU - Murdock, David R.

AU - Nicholas, Sarah K.

AU - Orengo, James P.

AU - Posey, Jennifer E.

AU - Potocki, Lorraine

AU - Rosenfeld, Jill A.

AU - Samson, Susan L.

AU - Scott, Daryl A.

AU - Tran, Alyssa A.

AU - Vogel, Tiphanie P.

AU - Wangler, Michael F.

AU - Yamamoto, Shinya

AU - Eng, Christine M.

AU - Liu, Pengfei

AU - Ward, Patricia A.

AU - Behrens, Edward

AU - Deardorff, Matthew

AU - Falk, Marni

AU - Hassey, Kelly

AU - Sullivan, Kathleen

AU - Vanderver, Adeline

AU - Goldstein, David B.

AU - Cope, Heidi

AU - Mcconkie-Rosell, Allyn

AU - Schoch, Kelly

AU - Shashi, Vandana

AU - Smith, Edward C.

AU - Spillmann, Rebecca C.

AU - Sullivan, Jennifer A.

AU - Tan, Queenie K.G.

AU - Walley, Nicole M.

AU - Agrawal, Pankaj B.

AU - Beggs, Alan H.

AU - Berry, Gerard T.

AU - Briere, Lauren C.

AU - Cobban, Laurel A.

AU - Coggins, Matthew

AU - Cooper, Cynthia M.

AU - Fieg, Elizabeth L.

AU - High, Frances

AU - Holm, Ingrid A.

AU - Korrick, Susan

AU - Krier, Joel B.

AU - Lincoln, Sharyn A.

AU - Loscalzo, Joseph

AU - Maas, Richard L.

AU - Macrae, Calum A.

AU - Pallais, J. Carl

AU - Rao, Deepak A.

AU - Rodan, Lance H.

AU - Silverman, Edwin K.

AU - Stoler, Joan M.

AU - Sweetser, David A.

AU - Walker, Melissa

AU - Walsh, Chris A.

AU - Esteves, Cecilia

AU - Kelley, Emily G.

AU - Kohane, Isaac S.

AU - Leblanc, Kimberly

AU - Mccray, Alexa T.

AU - Nagy, Anna

AU - Dasari, Surendra

AU - Lanpher, Brendan C.

AU - Lanza, Ian R.

AU - Morava, Eva

AU - Oglesbee, Devin

AU - Bademci, Guney

AU - Barbouth, Deborah

AU - Bivona, Stephanie

AU - Carrasquillo, Olveen

AU - Chang, Ta Chen Peter

AU - Forghani, Irman

AU - Grajewski, Alana

AU - Isasi, Rosario

AU - Lam, Byron

AU - Levitt, Roy

AU - Liu, Xue Zhong

AU - Mccauley, Jacob

AU - Sacco, Ralph

AU - Saporta, Mario

AU - Schaechter, Judy

AU - Tekin, Mustafa

AU - Telischi, Fred

AU - Thorson, Willa

AU - Zuchner, Stephan

AU - Colley, Heather A.

AU - Dayal, Jyoti G.

AU - Eckstein, David J.

AU - Findley, Laurie C.

AU - Krasnewich, Donna M.

AU - Mamounas, Laura A.

AU - Manolio, Teri A.

AU - Mulvihill, John J.

AU - Lamoure, Grace L.

AU - Goldrich, Madison P.

AU - Urv, Tiina K.

AU - Doss, Argenia L.

AU - Acosta, Maria T.

AU - Bonnenmann, Carsten

AU - D'souza, Precilla

AU - Draper, David D.

AU - Ferreira, Carlos

AU - Godfrey, Rena A.

AU - Groden, Catherine A.

AU - Macnamara, Ellen F.

AU - Maduro, Valerie V.

AU - Markello, Thomas C.

AU - Nath, Avi

AU - Novacic, Donna

AU - Pusey, Barbara N.

AU - Toro, Camilo

AU - Wahl, Colleen E.

AU - Baker, Eva

AU - Burke, Elizabeth A.

AU - Adams, David R.

AU - Gahl, William A.

AU - Malicdan, May Christine V.

AU - Tifft, Cynthia J.

AU - Wolfe, Lynne A.

AU - Yang, John

AU - Power, Bradley

AU - Gochuico, Bernadette

AU - Huryn, Laryssa

AU - Latham, Lea

AU - Davis, Joie

AU - Mosbrook-Davis, Deborah

AU - Rossignol, Francis

AU - Solomon, Ben

AU - Macdowall, John

AU - Thurm, Audrey

AU - Zein, Wadih

AU - Yousef, Muhammad

AU - Adam, Margaret

AU - Amendola, Laura

AU - Bamshad, Michael

AU - Beck, Anita

AU - Bennett, Jimmy

AU - Berg-Rood, Beverly

AU - Blue, Elizabeth

AU - Boyd, Brenna

AU - Byers, Peter

AU - Chanprasert, Sirisak

AU - Cunningham, Michael

AU - Dipple, Katrina

AU - Doherty, Daniel

AU - Earl, Dawn

AU - Glass, Ian

AU - Golden-Grant, Katie

AU - Hahn, Sihoun

AU - Hing, Anne

AU - Hisama, Fuki M.

AU - Horike-Pyne, Martha

AU - Jarvik, Gail P.

AU - Jarvik, Jeffrey

AU - Jayadev, Suman

AU - Lam, Christina

AU - Maravilla, Kenneth

AU - Mefford, Heather

AU - Merritt, J. Lawrence

AU - Mirzaa, Ghayda

AU - Nickerson, Deborah

AU - Raskind, Wendy

AU - Rosenwasser, Natalie

AU - Scott, C. Ron

AU - Sun, Angela

AU - Sybert, Virginia

AU - Wallace, Stephanie

AU - Wener, Mark

AU - Wenger, Tara

AU - Ashley, Euan A.

AU - Bejerano, Gill

AU - Bernstein, Jonathan A.

AU - Bonner, Devon

AU - Coakley, Terra R.

AU - Fernandez, Liliana

AU - Fisher, Paul G.

AU - Fresard, Laure

AU - Hom, Jason

AU - Huang, Yong

AU - Kohler, Jennefer N.

AU - Kravets, Elijah

AU - Majcherska, Marta M.

AU - Martin, Beth A.

AU - Marwaha, Shruti

AU - Mccormack, Colleen E.

AU - Raja, Archana N.

AU - Reuter, Chloe M.

AU - Ruzhnikov, Maura

AU - Sampson, Jacinda B.

AU - Smith, Kevin S.

AU - Sutton, Shirley

AU - Tabor, Holly K.

AU - Tucker, Brianna M.

AU - Wheeler, Matthew T.

AU - Zastrow, Diane B.

AU - Zhao, Chunli

AU - Byrd, William E.

AU - Crouse, Andrew B.

AU - Might, Matthew

AU - Nakano-Okuno, Mariko

AU - Whitlock, Jordan

AU - Brown, Gabrielle

AU - Butte, Manish J.

AU - Dell'angelica, Esteban C.

AU - Dorrani, Naghmeh

AU - Douine, Emilie D.

AU - Fogel, Brent L.

AU - Gutierrez, Irma

AU - Huang, Alden

AU - Krakow, Deborah

AU - Lee, Hane

AU - Loo, Sandra K.

AU - Mak, Bryan C.

AU - Martin, Martin G.

AU - Martínez-Agosto, Julian A.

AU - Mcgee, Elisabeth

AU - Nelson, Stanley F.

AU - Nieves-Rodriguez, Shirley

AU - Palmer, Christina G.S.

AU - Papp, Jeanette C.

AU - Parker, Neil H.

AU - Renteria, Genecee

AU - Signer, Rebecca H.

AU - Sinsheimer, Janet S.

AU - Wan, Jijun

AU - Wang, Lee Kai

AU - Perry, Katherine Wesseling

AU - Woods, Jeremy D.

AU - Alvey, Justin

AU - Andrews, Ashley

AU - Bale, Jim

AU - Bohnsack, John

AU - Botto, Lorenzo

AU - Carey, John

AU - Pace, Laura

AU - Longo, Nicola

AU - Marth, Gabor

AU - Moretti, Paolo

AU - Quinlan, Aaron

AU - Velinder, Matt

AU - Viskochi, Dave

AU - Bayrak-Toydemir, Pinar

AU - Mao, Rong

AU - Westerfield, Monte

AU - Bican, Anna

AU - Brokamp, Elly

AU - Duncan, Laura

AU - Hamid, Rizwan

AU - Kennedy, Jennifer

AU - Kozuira, Mary

AU - Newman, John H.

AU - Phillipsiii, John A.

AU - Rives, Lynette

AU - Robertson, Amy K.

AU - Solem, Emily

AU - Cogan, Joy D.

AU - Cole, F. Sessions

AU - Hayes, Nichole

AU - Kiley, Dana

AU - Sisco, Kathy

AU - Wambach, Jennifer

AU - Wegner, Daniel

AU - Baldridge, Dustin

AU - Pak, Stephen

AU - Schedl, Timothy

AU - Shin, Jimann

AU - Solnica-Krezel, Lilianna

AU - Sadjadi, Reza

AU - Elpeleg, Orly

AU - Lee, Chia Hsueh

AU - Bellen, Hugo J.

AU - Edvardson, Simon

AU - Eichler, Florian

AU - Dunn, Teresa M.

PY - 2023/4/1

Y1 - 2023/4/1

N2 - 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 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.

AB - 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 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.

KW - ORMDLs

KW - SPTSSA

KW - hereditary spastic paraplegia

KW - serine palmitoyltransferase

KW - sphingolipids

UR - http://www.scopus.com/inward/record.url?scp=85153121693&partnerID=8YFLogxK

U2 - 10.1093/brain/awac460

DO - 10.1093/brain/awac460

M3 - Article

C2 - 36718090

AN - SCOPUS:85153121693

SN - 0006-8950

VL - 146

SP - 1420

EP - 1435

JO - Brain

JF - Brain

IS - 4

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this