Immunofluorescence studies. Representative immunofluorescence micrographs of DAGLA in HEK293T cells transfected with either wild-type (WT) or mutant (dead) DAGLA cDNA (A) and in patient-derived fibroblasts (P) and control (C) from an unaffected individual (B). DAPI was used for nuclear plating. Scale bars = 50 µm. The accompanying bar graphs represent a quantitative estimate of the number of cells with perinuclear accumulation (arrows) or membrane-associated DAGLA (mmbr). Graphs: bars indicate mean and standard deviation error bars. The two-tailed Student’s test determined the P-values attributed to it: brain (2022). DOI: 10.1093/brain/awac223
In a study published in the October 2022 issue of brainresearchers from the Rady Children’s Institute of Genetic Medicine (RCIGM) and UCSD School of Medicine describe their discovery of a new clinical syndrome, DAGLA-associated optic nerve syndrome (NODRS), in children with termination variants in the diacylglycerol lipase alpha (DAGLA) gene that It encodes an enzyme in the brain involved in the signaling pathway of the endocannabinoid system (eCB).
In the study, the authors evaluated nine children from around the world who showed unique neurological-eye traits including developmental delays, difficulty with balance and walking, abnormal eye movements and head nodding. In each child, variants truncated in the last exon of DAGLA were found to be the cause of their unique pediatric syndrome. Because enzymatic activity maintained, the observed mislocalization of the truncated protein may explain the observed phenotype.
“Phenotype and genotype are very well correlated, which is unusual,” said Jennifer Friedman, MD, lead author of the study, clinical professor of neurosciences and pediatrics at UC San Diego and clinical investigator at RCIGM. “Collecting DAGLA pathogenic variants in these children may provide insight into the mechanism of the disease.”
DAGLA is a critical component of the eCB pathway, involved in a wide range of physiological functions. In the brain developmentThe eCB signaling pathway has important implications for neural development, signaling, and brain repair. In the mature nervous system, eCBs regulate short- and long-term suppression of neurotransmitter release. The pervasive nature of this pathway, and evolutionary conservation, have a central role in human health and disease. Despite this, no previously identified human disorders have been conclusively linked to mutations in the genes encoding components of this pathway so far.
“This is the first report linking a component of the endocannabinoid system, DAGLA, with a human genetic disorder, NODRS, and providing us with a better understanding of the role of endocannabinoids in health and disease,” said Dr. Friedman. “The mutation in DAGLA was initially identified by researchers at the Scripps Research Translational Institute.”
“This work is more than a description of a rare disease for children; it is the key wedge in a better understanding of how human health affected by cannabis; The results of this study may open the door to new cannabis-derived drugs for a wide range of disorders, because we know it cannabinoid receptors The eCB system is found throughout a person’s body, not just in the brain,” said Matthew Bainbridge, PhD, associate director of transformational research at RCIGM and lead author.
“This is an idea we haven’t considered before because we didn’t know the gene involved and the exact role of these receptors. Knowing the gene means knowing the pathway and the types of treatments that might be helpful.”
Dr. Bainbridge also believes that through diagnosis, parents of children living with NODRS now have the opportunity to come together as a community to share experiences, knowledge and hope with those who understand. Children with these types of symptoms should be diagnosed more easily now that the gene for this extremely rare disease has been identified. Dr Bainbridge concluded: “It is time for a genetic mutation linking the endocannabinoid system to human disease.”
Endocannabinoid dysfunction in neurological diseases: DAGLA-associated neuroocular syndrome, brain (2022). DOI: 10.1093/brain/awac223
Presented by the Rady Children’s Institute of Genetic Medicine
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