Seven unique DAGLA variants identified in nine children from eight families. All variants lead to premature protein truncation proximally in the final exon and disrupt multiple predicted phosphorylation sites and a protein-protein interaction domain with HOMER scaffolding proteins. Mutations where outside the alpha/beta hydrolase domain and had no effect on DAGLA enzymatic activity. The defect could be du to mis-localized DAGLA. Patients showed a neuro-ocular phenotype characterized by developmental delay, ataxia, and complex oculomotor abnormality with paroxysms of nystagmus or eye deviation accompanied by compensatory head posture and worsened incoordination most frequently after waking.
The endocannabinoid system is a highly conserved and ubiquitous signaling 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. RNAseq 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 pediatric syndrome. Because enzymatic activity was preserved, the observed mis-localization 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.