Endocannabinoid dysfunction in neurological disease: neuro-ocular DAGLA-related syndrome
Authors: Bainbridge Matthew N , Mazumder Aloran , Ogasawara Daisuke , Abou Jamra Rami , Bernard Geneviève , Bertini Enrico , Burglen Lydie , Cope Heidi , Crawford Ali , Derksen Alexa , Dure Leon , Gantz Emily , Koch-Hogrebe Margarete , Hurst Anna C E , Mahida Sonal , Marshall Paige , Micalizzi Alessia , Novelli Antonio , Peng Hongfan ,   Rady Children's Institute for Genomic Medicine, Rodriguez Diana , Robbins Shira L , Rutledge S Lane , Scalise Roberta , Schließke Sophia , Shashi Vandana , Srivastava Siddharth , Thiffault Isabella , Topol Sarah ,   Undiagnosed Disease Network, Acosta Maria T , Adam Margaret , Adams David R , Alvey Justin , Amendola Laura , Andrews Ashley , Ashley Euan A , Azamian Mahshid S , Bacino Carlos A , Bademci Guney , Balasubramanyam Ashok , Baldridge Dustin , Bale Jim , Bamshad Michael , Barbouth Deborah , Bayrak-Toydemir Pinar , Beck Anita , Beggs Alan H , Behrens Edward , Bejerano Gill , Bennet Jimmy , Berg-Rood Beverly , Bernstein Jonathan A , Berry Gerard T , Bican Anna , Bivona Stephanie , Blue Elizabeth , Bohnsack John , Bonner Devon , Botto Lorenzo , Boyd Brenna , Briere Lauren C , Brokamp Elly , Brown Gabrielle , Burke Elizabeth A , Burrage Lindsay C , Butte Manish J , Byers Peter , Byrd William E , Carey John , Carrasquillo Olveen , Cassini Thomas , Chang Ta Chen Peter , Chanprasert Sirisak , Chao Hsiao-Tuan , Clark Gary D , Coakley Terra R , Cobban Laurel A , Cogan Joy D , Coggins Matthew , Cole F Sessions , Colley Heather A , Cooper Cynthia M , Cope Heidi , Craigen William J , Crouse Andrew B , Cunningham Michael , D’Souza Precilla , Dai Hongzheng , Dasari Surendra , Davis Joie , Dayal Jyoti G , Deardorff Matthew , Dell’Angelica Esteban C , Dipple Katrina , Doherty Daniel , Dorrani Naghmeh , Doss Argenia L , Douine Emilie D , Duncan Laura , Earl Dawn , Eckstein David J , Emrick Lisa T , Eng Christine M , Esteves Cecilia , Falk Marni , Fernandez Liliana , Fieg Elizabeth L , Fisher Paul G , Fogel Brent L , Forghani Irman , Gahl William A , Glass Ian , Gochuico Bernadette , Godfrey Rena A , Golden-Grant Katie , Goldrich Madison P , Grajewski Alana , Gutierrez Irma , Hadley Don , Hahn Sihoun , Hamid Rizwan , Hassey Kelly , Hayes Nichole , High Frances , Hing Anne , Hisama Fuki M , Holm Ingrid A , Hom Jason , Horike-Pyne Martha , Huang Alden , Huang Yong , Introne Wendy , Isasi Rosario , Izumi Kosuke , Jamal Fariha , Jarvik Gail P , Jarvik Jeffrey , Jayadev Suman , Jean-Marie Orpa , Jobanputra Vaidehi , Karaviti Lefkothea , Kennedy Jennifer , Ketkar Shamika , Kiley Dana , Kilich Gonench , Kobren Shilpa N , Kohane Isaac S , Kohler Jennefer N , Krakow Deborah , Krasnewich Donna M , Kravets Elijah , Korrick Susan , Koziura Mary , Lalani Seema R , Lam Byron , Lam Christina , LaMoure Grace L , Lanpher Brendan C , Lanza Ian R , LeBlanc Kimberly , Lee Brendan H , Levitt Roy , Lewis Richard A , Liu Pengfei , Liu Xue Zhong , Longo Nicola , Loo Sandra K , Loscalzo Joseph , Maas Richard L , Macnamara Ellen F , MacRae Calum A , Maduro Valerie V , Mak Bryan C , Malicdan May Christine V , Mamounas Laura A , Manolio Teri A , Mao Rong , Maravilla Kenneth , Marom Ronit , Marth Gabor , Martin Beth A , Martin Martin G , Martínez-Agosto Julian A , Marwaha Shruti , McCauley Jacob , McConkie-Rosell Allyn , McCray Alexa T , McGee Elisabeth , Mefford Heather , Merritt J Lawrence , Might Matthew , Mirzaa Ghayda , Morava Eva , Moretti Paolo M , Nakano-Okuno Mariko , Nelson Stan F , Newman John H , Nicholas Sarah K , Nickerson Deborah , Nieves-Rodriguez Shirley , Novacic Donna , Oglesbee Devin , Orengo James P , Pace Laura , Pak Stephen , Pallais J Carl , Palmer Christina G S , Papp Jeanette C , Parker Neil H , III John A Phillips , Posey Jennifer E , Potocki Lorraine , Pusey Barbara N , Quinlan Aaron , Raskind Wendy , Raja Archana N , Rao Deepak A , Raper Anna , Renteria Genecee , Reuter Chloe M , Rives Lynette , Robertson Amy K , Rodan Lance H , Rosenfeld Jill A , Rosenwasser Natalie , Rossignol Francis , Ruzhnikov Maura , Sacco Ralph , Sampson Jacinda B , Saporta Mario , Scott C Ron , Schaechter Judy , Schedl Timothy , Schoch Kelly , Scott Daryl A , Shashi Vandana , Shin Jimann , Silverman Edwin K , Sinsheimer Janet S , Sisco Kathy , Smith Edward C , Smith Kevin S , Solem Emily , Solnica-Krezel Lilianna , Solomon Ben , Spillmann Rebecca C , Stoler Joan M , Sullivan Jennifer A , Sullivan Kathleen , Sun Angela , Sutton Shirley , Sweetser David A , Sybert Virginia , Tabor Holly K , Tan Amelia L M , Tan Queenie K-G , Tekin Mustafa , Telischi Fred , Thorson Willa , Tifft Cynthia J , Toro Camilo , Tran Alyssa A , Tucker Brianna M , Urv Tiina K , Vanderver Adeline , Velinder Matt , Viskochil Dave , Vogel Tiphanie P , Wahl Colleen E , Wallace Stephanie , Walley Nicole M , Walker Melissa , Wambach Jennifer , Wan Jijun , Wang Lee-kai , Wangler Michael F , Ward Patricia A , Wegner Daniel , Weisz-Hubshman Monika , Wener Mark , Wenger Tara , Perry Katherine Wesseling , Westerfield Monte , Wheeler Matthew T , Whitlock Jordan , Wolfe Lynne A , Worley Kim , Xiao Changrui , Yamamoto Shinya , Yang John , Zastrow Diane B , Zhang Zhe , Zhao Chunli , Zuchner Stephan , Bellen Hugo , Mahoney Rachel , Qebibo Leila , Wieczorek Dagmar , Cravatt Benjamin , Haricharan Svasti , Torkamani Ali , Friedman Jennifer 
Published: June 2022

The endocannabinoid system is a highly conserved and ubiquitous signalling pathway with broad-ranging effects. Despite critical pathway functions, gene variants have not previously been conclusively linked to human disease.

We identified nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. All children displayed paroxysms of nystagmus or eye deviation accompanied by compensatory head posture and worsened incoordination most frequently after waking. RNA sequencing showed clear expression of the truncated transcript and no differences were found between mutant and wild-type DAGLA activity. Immunofluorescence staining of patient-derived fibroblasts and HEK cells expressing the mutant protein showed distinct perinuclear aggregation not detected in control samples.

This report establishes truncating variants in the last DAGLA exon as the cause of a unique paediatric syndrome. Because enzymatic activity was preserved, the observed mislocalization of the truncated protein may account for the observed phenotype. Potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect. To our knowledge, this is the first report directly linking an endocannabinoid system component with human genetic disease and sets the stage for potential future therapeutic avenues.