Loss of the endoplasmic reticulum protein Tmem208 affects cell polarity, development, and viability
Authors: Dutta Debdeep , Kanca Oguz , Shridharan Rishi V. , Marcogliese Paul C. , Steger Benjamin , Morimoto Marie , Frost F. Graeme , Macnamara Ellen ,   Undiagnosed Diseases Network, Wangler Michael F. , Yamamoto Shinya , Jenny Andreas , Adams David , Malicdan May C. , Bellen Hugo J. , Alejandro Mercedes E. , Azamian Mahshid S. , Bacino Carlos A. , Balasubramanyam Ashok , Bellen Hugo J. , Burrage Lindsay C. , Chao Hsiao-Tuan , Clark Gary D. , Craigen William J. , Dai Hongzheng , Jamal Fariha , Karaviti Lefkothea , Ketkar Shamika , Lee Brendan H. , Lewis Richard A. , Marom Ronit , Moretti Paolo M. , Nicholas Sarah K. , Orengo James P. , Posey Jennifer E. , Potocki Lorraine , Scott Daryl A. , Tran Alyssa A. , Vogel Tiphanie P. , Hubshman Monika Weisz , Worley Kim , Wangler Michael F. , Yamamoto Shinya , Eng Christine M. , Liu Pengfei , Ward Patricia A. , Behrens Edward , Izumi Kosuke , Falk Marni , Hassey Kelly , Sullivan Kathleen , Raper Anna , Kilich Gonench , Zhang Zhe , 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. , 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 , Kohane Isaac S. , LeBlanc Kimberly , McCray Alexa T. , Kobren Shilpa N. , Tan Amelia L. M. , Mahoney Rachel , Dasari Surendra , Lanpher Brendan C. , Lanza Ian R. , Morava Eva , Oglesbee Devin , Bademci Guney , Barbouth Deborah , Bivona Stephanie , Carrasquillo Olveen , Chang Ta Chen Pete , 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 , Godfreyv 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 Michae , 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 , RonScott C. , 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. , Hom Jason , Huang Yong , Kohler Jennefer N. , Kravets Elijah , Martin Beth A. , Marwaha Shruti , 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 , Viskochil Dave , Bayrak-Toydemir Pinar , Mao Rong , Westerfield Monte , Bican Anna , Brokamp Elly , Duncan Laura , Hamid Rizwan , Kennedy Jennifer , Kozuira Mary , Newman John H. , Phillips John A. , Rives Lynette , Robertson Amy K. , Solem Emily , Cogan Joy D. , Sessions Cole F. , Hayes Nichole , Kiley Dana , Sisco Kathy , Wambach Jennifer , Wegner Daniel , Baldridge Dustin , Pak Stephen , Schedl Timothy , Shin Jimann , Solnica-Krezel Lilianna 
Published: February 2024

Nascent proteins destined for the cell membrane and the secretory pathway are targeted to the endoplasmic reticulum (ER) either posttranslationally or cotranslationally. The signal-independent pathway, containing the protein TMEM208, is one of three pathways that facilitates the translocation of nascent proteins into the ER. The in vivo function of this protein is ill characterized in multicellular organisms. Here, we generated a CRISPR-induced null allele of the fruit fly orthologCG8320/Tmem208by replacing the gene with theKozak-GAL4sequence. We show thatTmem208is broadly expressed in flies and that its loss causes lethality, although a few short-lived flies eclose. These animals exhibit wing and eye developmental defects consistent with impaired cell polarity and display mild ER stress. Tmem208 physically interacts with Frizzled (Fz), a planar cell polarity (PCP) receptor, and is required to maintain proper levels of Fz. Moreover, we identified a child with compound heterozygous variants inTMEM208who presents with developmental delay, skeletal abnormalities, multiple hair whorls, cardiac, and neurological issues, symptoms that are associated with PCP defects in mice and humans. Additionally, fibroblasts of the proband display mild ER stress. Expression of the reference humanTMEM208in flies fully rescues the loss ofTmem208, and the two proband-specific variants fail to rescue, suggesting that they are loss-of-function alleles. In summary, our study uncovers a role of TMEM208 in development, shedding light on its significance in ER homeostasis and cell polarity.