Endocannabinoid dysfunction in neurological disease: neuro-ocular DAGLA-related syndrome

Author:

Bainbridge Matthew N1,Mazumder Aloran2,Ogasawara Daisuke3,Abou Jamra Rami4,Bernard Geneviève56789,Bertini Enrico10ORCID,Burglen Lydie1112,Cope Heidi13,Crawford Ali14,Derksen Alexa59,Dure Leon15,Gantz Emily15,Koch-Hogrebe Margarete16,Hurst Anna C E17,Mahida Sonal18,Marshall Paige18,Micalizzi Alessia19,Novelli Antonio19,Peng Hongfan3,Rodriguez Diana20,Robbins Shira L21,Rutledge S Lane1517,Scalise Roberta2223,Schließke Sophia4,Shashi Vandana13,Srivastava Siddharth18ORCID,Thiffault Isabella242526ORCID,Topol Sarah3,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 Leila11,Wieczorek Dagmar27,Cravatt Benjamin3,Haricharan Svasti2ORCID,Torkamani Ali3ORCID,Friedman Jennifer1282930ORCID, ,

Affiliation:

1. Rady Children’s Institute for Genomic Medicine (RCIGM) , San Diego, CA 92123 , USA

2. Sanford Burnham Prebys Medical Discovery Institute , La Jolla, CA 92037 , USA

3. The Scripps Research Translational Institute, The Scripps Research Institute , La Jolla, CA 92037 , USA

4. Institute of Human Genetics, University Medical Center Leipzig , Leipzig 04103 , Germany

5. Department of Neurology and Neurosurgery, McGill University , Montreal , Canada

6. Department of Pediatrics and Human Genetics, McGill University , Montreal , Canada

7. Department of Human Genetics, McGill University , Montreal , Canada

8. Department Specialized Medicine, Division of Medical Genetics, McGill University Health Center , Montreal , Canada

9. Child Health and Human Development Program, Research Institute of the McGill University Health Center , Montreal , Canada

10. Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences ‘Bambino Gesu’ Children’s Research Hospital, IRCCS , Rome , Italy

11. Centre de Référence Malformations et Maladies Congénitales du Cervelet, Département de génétique, AP-HP Sorbonne Université, Hôpital Trousseau , Paris , France

12. Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163 , Paris , France

13. Department of Pediatrics, Division Medical Genetics Durham, Duke University Medical Center , North Carolina , USA

14. Illumina , San Diego, CA 92122 , USA

15. Division of Pediatric Neurology, Department of Pediatrics, University of Alabama at Birmingham , Birmingham, AL 35233 , USA

16. Vestische Kinder- und Jugendklinik , 45711 Datteln , Germany

17. Department of Genetics, University of Alabama at Birmingham , Birmingham, Alabama , USA

18. Department of Neurology, Boston Children’s Hospital , Boston, Massachusetts , USA

19. Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS , Roma , Italy

20. Sorbonne Université, INSERM UMR 1141, AP-HP.SU, Centre de Référence Maladies Rares Malformations et Maladies Congénitales du Cervelet & Service de Neuropédiatrie, Hôpital Trousseau , Paris , France

21. Ratner Children’s Eye Center at the Shiley Eye Institute; Viterbi Family Department of Ophthalmology, University of California San Diego , La Jolla, CA 92093 , USA

22. Department of Developmental Neuroscience, IRCCS Stella Maris Foundation , Pisa , Italy

23. Tuscan PhD Program of Neuroscience, University of Florence, Pisa and Siena, Florence , Italy

24. Genomic Medicine Center, Children’s Mercy Hospital , Kansas City, Missouri , USA

25. Faculty of Medicine, University of Missouri Kansas City , Kansas City, Missouri , USA

26. Department of Pathology, Children’s Mercy Hospital , Kansas City, Missouri , USA

27. Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf , 40225, Düsseldorf , Germany

28. Division of Neurology, Rady Children’s Hospital San Diego , CA 92123 , USA

29. Department of Neurosciences, University of California La Jolla , CA 92037 , USA

30. Department of Pediatrics, University of California La Jolla , CA 92037 , USA

Abstract

Abstract 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.

Funder

Clinical and Translational Science Award

NIH-NINDS

NIH Common Fund

National Institutes of Health

Canadian Institute of Health Research

Fonds de Recherche du Quebec – Sant

Canadian Institutes of Health Research

Canadian Institutes for Health Research

Fondation du Grand défi Pierre Lavoie and Healthy Brains for Healthy Lives

NCATS

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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