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AGC1 deficiency and calcium signaling in mitochondria: a new disease model for the study of pathogenic mechanisms and for the development of therapeutic strategies

18th national competition for scientific and technical research

Rare diseases

Senior Researcher : Jorgina Satrústegui Gil-Delgado

Research Centre or Institution : Centro de Biología Molecular "Severo Ochoa". CSIC-Universidad Autónoma de Madrid


AGC1 deficiency is an autosomal recessive rare disease associated with growth defects, impaired neurodevelopment, epilepsy and hypomyelination, caused by mutations in the SlC25A12/ARALAR/AGC1 gene. The mouse model for this disease, the AGC1-KO mouse, has a very severe phenotype, which has precluded testing diets or treatments for the disease in the mouse. The present project aimed at producing an ARALAR deficient mouse with a milder phenotype. A mouse with four point mutations in the Ca2+ binding motifs of ARALAR/AGC1 was obtained. Surprisingly, this mutant mouse (Aralar 4mut/Aralar 4mut) had a phenotype just as severe as the global AGC1-KO mouse. The levels of 4mutARALAR protein were very low in key tissues such as the brain, heart, and MEFs, but not in N2A cells, while mRNA levels were not affected. Inhibition of the proteasome, or inhibition of the metalloproteases of the intermembrane space did not rescue 4mutARALAR levels in (Aralar 4mut/Aralar 4mut) MEFs, suggesting that increased degradation of mutant protein was not the cause of the phenotype. The results suggest that failure to express 4mutARALAR protein is probably caused by an impaired translation possibly associated with the structural change imposed by the mutation and indicate that pathogenic mutations in Aralar affecting residues within the Ca2+ binding domain may also cause a lack of the protein. 

As a ketogenic diet was not feasible in AGC1-KO mice, we have studied the direct administration of β-hydroxybutyrate (βOHB), the main ketone body produced by ketogenic diets. We found that βOHB increases the respiratory responses to glutamate in AGC1-KO neurons in culture, and survival to glutamate excitotoxicity. In vivo, the effect of a 5 day treatment with βOHB led to a striking recovery of myelin proteins and striatal dopamine markers. These results open up the possibility of using βOHB directly as a diet component to treat ARALAR/AGC1 deficiency.


Scientific Production
Magazine Articles 5
Communications at national conferences 8
Communications at international conferences 9


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