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


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.

SUBMITTER: Bainbridge MN 

PROVIDER: S-EPMC9586540 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Bainbridge Matthew N MN   Mazumder Aloran A   Ogasawara Daisuke D   Abou Jamra Rami R   Bernard Geneviève G   Bertini Enrico E   Burglen Lydie L   Cope Heidi H   Crawford Ali A   Derksen Alexa A   Dure Leon L   Gantz Emily E   Koch-Hogrebe Margarete M   Hurst Anna C E ACE   Mahida Sonal S   Marshall Paige P   Micalizzi Alessia A   Novelli Antonio A   Peng Hongfan H   Rodriguez Diana D   Robbins Shira L SL   Rutledge S Lane SL   Scalise Roberta R   Schließke Sophia S   Shashi Vandana V   Srivastava Siddharth S   Thiffault Isabella I   Topol Sarah S   Qebibo Leila L   Wieczorek Dagmar D   Cravatt Benjamin B   Haricharan Svasti S   Torkamani Ali A   Friedman Jennifer J  

Brain : a journal of neurology 20221001 10


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 nystagmu  ...[more]

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