@article{86562bb6277e4074914e62fe9a93fa99,
title = "Dominant missense variants in SREBF2 are associated with complex dermatological, neurological, and skeletal abnormalities",
abstract = "Purpose: We identified 2 individuals with de novo variants in SREBF2 that disrupt a conserved site 1 protease (S1P) cleavage motif required for processing SREBP2 into its mature transcription factor. These individuals exhibit complex phenotypic manifestations that partially overlap with sterol regulatory element binding proteins (SREBP) pathway-related disease phenotypes, but SREBF2-related disease has not been previously reported. Thus, we set out to assess the effects of SREBF2 variants on SREBP pathway activation. Methods: We undertook ultrastructure and gene expression analyses using fibroblasts from an affected individual and utilized a fly model of lipid droplet (LD) formation to investigate the consequences of SREBF2 variants on SREBP pathway function. Results: We observed reduced LD formation, endoplasmic reticulum expansion, accumulation of aberrant lysosomes, and deficits in SREBP2 target gene expression in fibroblasts from an affected individual, indicating that the SREBF2 variant inhibits SREBP pathway activation. Using our fly model, we discovered that SREBF2 variants fail to induce LD production and act in a dominant-negative manner, which can be rescued by overexpression of S1P. Conclusion: Taken together, these data reveal a mechanism by which SREBF2 pathogenic variants that disrupt the S1P cleavage motif cause disease via dominant-negative antagonism of S1P, limiting the cleavage of S1P targets, including SREBP1 and SREBP2.",
keywords = "Drosophila, Lipid droplet, S1P, SREBF1, SREBF2",
author = "{Undiagnosed Diseases Network} and Moulton, {Matthew J.} and Kristhen Atala and Yiming Zheng and Debdeep Dutta and Grange, {Dorothy K.} and Lin, {Wen Wen} and Wegner, {Daniel J.} and Wambach, {Jennifer A.} and Duker, {Angela L.} and Bober, {Michael B.} and Lisa Kratz and Wise, {Carol A.} and Ila Oxendine and Anas Khanshour and Bacino, {Carlos A.} and Ashok Balasubramanyam and Burrage, {Lindsay C.} and Chao, {Hsiao Tuan} and Ivan Chinn and Clark, {Gary D.} and Craigen, {William J.} and Hongzheng Dai and Emrick, {Lisa T.} and Shamika Ketkar and Lalani, {Seema R.} and Lee, {Brendan H.} and Lewis, {Richard A.} and Ronit Marom and Orengo, {James P.} and Posey, {Jennifer E.} and Lorraine Potocki and Rosenfeld, {Jill A.} and Elaine Seto and Scott, {Daryl A.} and Arjun Tarakad and Tran, {Alyssa A.} and Vogel, {Tiphanie P.} and Hubshman, {Monika Weisz} and Kim Worley and Bellen, {Hugo J.} and Wangler, {Michael F.} and Shinya Yamamoto and Oguz Kanca and Eng, {Christine M.} and Pengfei Liu and Ward, {Patricia A.} and Edward Behrens and Marni Falk and Kelly Hassey and Kosuke Izumi and Gonench Kilich and Kathleen Sullivan and Adeline Vanderver and Zhe Zhang and Anna Raper and Vaidehi Jobanputra and Mohamad Mikati and Allyn McConkie-Rosell and Kelly Schoch and Vandana Shashi and Spillmann, {Rebecca C.} and Tan, {Queenie K.G.} and Walley, {Nicole M.} and Beggs, {Alan H.} and Berry, {Gerard T.} and Briere, {Lauren C.} and Cobban, {Laurel A.} and Matthew Coggins and Fieg, {Elizabeth L.} and Frances High and Holm, {Ingrid A.} and Susan Korrick 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 Jessica Douglas and Emily Glanton and Kobren, {Shilpa N.} and Kohane, {Isaac S.} and Kimberly LeBlanc and Maghiro, {Audrey Stephannie C.} and Rachel Mahoney and McCray, {Alexa T.} and Tan, {Amelia L.M.} 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 Nicholas Borja and Gonzalez, {Joanna M.} and Kumarie Latchman and Peart, {L{\'e}Shon S.} and Adriana Rebelo and Smith, {Carson A.} and Mustafa Tekin and Willa Thorson and Stephan Zuchner and Herman Taylor and Colley, {Heather A.} and Dayal, {Jyoti G.} and Doss, {Argenia L.} and Eckstein, {David J.} and Sarah Hutchison and Krasnewich, {Donna M.} and Mamounas, {Laura A.} and Manolio, {Teri A.} and Urv, {Tiina K.} and Acosta, {Maria T.} and Precilla D'Souza and Andrea Gropman and Macnamara, {Ellen F.} and Maduro, {Valerie V.} and Mulvihill, {John J.} and Donna Novacic and {Pusey Swerdzewski}, {Barbara N.} and Camilo Toro and Wahl, {Colleen E.} and Adams, {David R.} and Ben Afzali and Burke, {Elizabeth A.} and Joie Davis and Margaret Delgado and Jiayu Fu and Gahl, {William A.} and Neil Hanchard and Yan Huang and Wendy Introne and Orpa Jean-Marie and Malicdan, {May Christine V.} and Marie Morimoto and Leoyklang Petcharet and Francis Rossignol and Marla Sabaii and Ben Solomon and Tifft, {Cynthia J.} and Wolfe, {Lynne A.} and Heidi Wood and Aimee Allworth and Michael Bamshad and Anita Beck and Jimmy Bennett and Elizabeth Blue and Peter Byers and Sirisak Chanprasert and Michael Cunningham and Katrina Dipple and Daniel Doherty and Dawn Earl and Ian Glass and Anne Hing and Hisama, {Fuki M.} and Martha Horike-Pyne and Jarvik, {Gail P.} and Jeffrey Jarvik and Suman Jayadev and Emerald Kaitryn and Christina Lam and Danny Miller and Ghayda Mirzaa and Wendy Raskind and Elizabeth Rosenthal and Emily Shelkowitz and Sam Sheppeard and Andrew Stergachis and Virginia Sybert and Mark Wener and Tara Wenger and Alvarez, {Raquel L.} and Gill Bejerano and Bernstein, {Jonathan A.} and Devon Bonner and Coakley, {Terra R.} and Fisher, {Paul G.} and Goddard, {Page C.} and Halley, {Meghan C.} and Jason Hom and Kohler, {Jennefer N.} and Elijah Kravets and Martin, {Beth A.} and Shruti Marwaha and Reuter, {Chloe M.} and Maura Ruzhnikov and Sampson, {Jacinda B.} and Smith, {Kevin S.} and Dustin Baldridge and Stephen Pak and Timothy Schedl and Jimann Shin and Lilianna Solnica-Krezel",
note = "Publisher Copyright: {\textcopyright} 2024 American College of Medical Genetics and Genomics",
year = "2024",
month = sep,
doi = "10.1016/j.gim.2024.101174",
language = "English",
volume = "26",
journal = "Genetics in Medicine",
issn = "1098-3600",
number = "9",
}