SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia
Authors: Srivastava Siddharth , Shaked Hagar Mor , Gable Kenneth , Gupta Sita D , Pan Xueyang , Somashekarappa Niranjanakumari , Han Gongshe , Mohassel Payam , Gotkine Marc , Doney Elizabeth , Goldenberg Paula , Tan Queenie K G , Gong Yi , Kleinstiver Benjamin , Wishart Brian , Cope Heidi , Pires Claudia Brito , Stutzman Hannah , Spillmann Rebecca C ,   Undiagnosed Disease Network, Alejandro Mercedes E , Azamian Mahshid S , Bacino Carlos A , Balasubramanyam Ashok , Burrage Lindsay C , Chao Hsiao-Tuan , Clark Gary D , Craigen William J , Dai Hongzheng , Dhar Shweta U , Emrick Lisa T , Goldman Alica M , Hanchard Neil A , Jamal Fariha , Karaviti Lefkothea , Lalani Seema R , Lee Brendan H , Lewis Richard A , Marom Ronit , Moretti Paolo M , Murdock David R , Nicholas Sarah K , Orengo James P , Posey Jennifer E , Potocki Lorraine , Rosenfeld Jill A , Samson Susan L , Scott Daryl A , Tran Alyssa A , Vogel Tiphanie P , Wangler Michael F , Yamamoto Shinya , Eng Christine M , Liu Pengfei , Ward Patricia A , Behrens Edward , Deardorff Matthew , Falk Marni , Hassey Kelly , Sullivan Kathleen , Vanderver Adeline , Goldstein David B , Cope Heidi , McConkie-Rosell Allyn , Schoch Kelly , Shashi Vandana , Smith Edward C , Spillmann Rebecca C , Sullivan Jennifer A , Tan Queenie K-G , Walley Nicole M , Agrawal Pankaj B , Beggs Alan H , Berry Gerard T , Briere Lauren C , Cobban Laurel A , Coggins Matthew , Cooper Cynthia M , Fieg Elizabeth L , High Frances , Holm Ingrid A , Korrick Susan , Krier Joel B , Lincoln Sharyn A , Loscalzo Joseph , Maas Richard L , MacRae Calum A , Pallais J Carl , Rao Deepak A , Rodan Lance H , Silverman Edwin K , Stoler Joan M , Sweetser David A , Walker Melissa , Walsh Chris A , Esteves Cecilia , Kelley Emily G , Kohane Isaac S , LeBlanc Kimberly , McCray Alexa T , Nagy Anna , Dasari Surendra , Lanpher Brendan C , Lanza Ian R , Morava Eva , Oglesbee Devin , Bademci Guney , Barbouth Deborah , Bivona Stephanie , Carrasquillo Olveen , Chang Ta Chen Peter , Forghani Irman , Grajewski Alana , Isasi Rosario , Lam Byron , Levitt Roy , Liu Xue Zhong , McCauley Jacob , Sacco Ralph , Saporta Mario , Schaechter Judy , Tekin Mustafa , Telischi Fred , Thorson Willa , Zuchner Stephan , Colley Heather A , Dayal Jyoti G , Eckstein David J , Findley Laurie C , Krasnewich Donna M , Mamounas Laura A , Manolio Teri A , Mulvihill John J , LaMoure Grace L , Goldrich Madison P , Urv Tiina K , Doss Argenia L , Acosta Maria T , Bonnenmann Carsten , D’Souza Precilla , Draper David D , Ferreira Carlos , Godfrey Rena A , Groden Catherine A , Macnamara Ellen F , Maduro Valerie V , Markello Thomas C , Nath Avi , Novacic Donna , Pusey Barbara N , Toro Camilo , Wahl Colleen E , Baker Eva , Burke Elizabeth A , Adams David R , Gahl William A , Malicdan May Christine V , Tifft Cynthia J , Wolfe Lynne A , Yang John , Power Bradley , Gochuico Bernadette , Huryn Laryssa , Latham Lea , Davis Joie , Mosbrook-Davis Deborah , Rossignol Francis , Solomon Ben , MacDowall John , Thurm Audrey , Zein Wadih , Yousef Muhammad , Adam Margaret , Amendola Laura , Bamshad Michael , Beck Anita , Bennett Jimmy , Berg-Rood Beverly , Blue Elizabeth , Boyd Brenna , Byers Peter , Chanprasert Sirisak , Cunningham Michael , Dipple Katrina , Doherty Daniel , Earl Dawn , Glass Ian , Golden-Grant Katie , Hahn Sihoun , Hing Anne , Hisama Fuki M , Horike-Pyne Martha , Jarvik Gail P , Jarvik Jeffrey , Jayadev Suman , Lam Christina , Maravilla Kenneth , Mefford Heather , Merritt J Lawrence , Mirzaa Ghayda , Nickerson Deborah , Raskind Wendy , Rosenwasser Natalie , Scott C Ron , Sun Angela , Sybert Virginia , Wallace Stephanie , Wener Mark , Wenger Tara , Ashley Euan A , Bejerano Gill , Bernstein Jonathan A , Bonner Devon , Coakley Terra R , Fernandez Liliana , Fisher Paul G , Fresard Laure , Hom Jason , Huang Yong , Kohler Jennefer N , Kravets Elijah , Majcherska Marta M , Martin Beth A , Marwaha Shruti , McCormack Colleen E , Raja Archana N , Reuter Chloe M , Ruzhnikov Maura , Sampson Jacinda B , Smith Kevin S , Sutton Shirley , Tabor Holly K , Tucker Brianna M , Wheeler Matthew T , Zastrow Diane B , Zhao Chunli , Byrd William E , Crouse Andrew B , Might Matthew , Nakano-Okuno Mariko , Whitlock Jordan , Brown Gabrielle , Butte Manish J , Dell’Angelica Esteban C , Dorrani Naghmeh , Douine Emilie D , Fogel Brent L , Gutierrez Irma , Huang Alden , Krakow Deborah , Lee Hane , Loo Sandra K , Mak Bryan C , Martin Martin G , Martínez-Agosto Julian A , McGee Elisabeth , Nelson Stanley F , Nieves-Rodriguez Shirley , Palmer Christina G S , Papp Jeanette C , Parker Neil H , Renteria Genecee , Signer Rebecca H , Sinsheimer Janet S , Wan Jijun , Wang Lee-kai , Perry Katherine Wesseling , Woods Jeremy D , Alvey Justin , Andrews Ashley , Bale Jim , Bohnsack John , Botto Lorenzo , Carey John , Pace Laura , Longo Nicola , Marth Gabor , Moretti Paolo , Quinlan Aaron , Velinder Matt , Viskochi Dave , Bayrak-Toydemir Pinar , Mao Rong , Westerfield Monte , Bican Anna , Brokamp Elly , Duncan Laura , Hamid Rizwan , Kennedy Jennifer , Kozuira Mary , Newman John H , PhillipsIII John A , Rives Lynette , Robertson Amy K , Solem Emily , Cogan Joy D , Cole F Sessions , Hayes Nichole , Kiley Dana , Sisco Kathy , Wambach Jennifer , Wegner Daniel , Baldridge Dustin , Pak Stephen , Schedl Timothy , Shin Jimann , Solnica-Krezel Lilianna , Sadjadi Reza , Elpeleg Orly , Lee Chia-Hsueh , Bellen Hugo J , Edvardson Simon , Eichler Florian , Dunn Teresa M 
Published: January 2023

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.