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Recessive HACE1 mutations are associated with a severe neurodevelopmental disorder (OMIM: 616756). However, the physiopathologycal bases of the disease are yet to be completely clarified. Whole-exome sequencing identified homozygous HACE1 mutations (c.240C&gt;A, p.Cys80Ter) in a patient with brain atrophy, psychomotor retardation and 3-methylglutaconic aciduria, a biomarker of mitochondrial dysfunction. To elucidate the pathomechanisms underlying HACE1 deficiency, a comprehensive molecular analysis was performed in patient fibroblasts. Western Blot demonstrated the deleterious effect of the mutation, as the complete absence of HACE1 protein was observed. Immunofluorescence studies showed an increased number of LC3 puncta together with the normal initiation of the autophagic cascade, indicating a reduction in the autophagic flux. Oxidative stress response was also impaired in HACE1 fibroblasts, as shown by the reduced NQO1 and Hmox1 mRNA levels observed in H 2 O 2 -treated cells. High levels of lipid peroxidation, consistent with accumulated oxidative damage, were also detected. Although the patient phenotype could resemble a mitochondrial defect, the analysis of the mitochondrial function showed no major abnormalities. However, an important increase in mitochondrial oxidative stress markers and a strong reduction in the mitophagic flux were observed, suggesting that the recycling of damaged mitochondria might be targeted in HACE1 cells. In summary, we demonstrate for the first time that the impairment of autophagy, mitophagy and oxidative damage response might be involved in the pathogenesis of HACE1 deficiency.

Physiopathological Bases of the Disease Caused by HACE1 Mutations: Alterations in Autophagy, Mitophagy and Oxidative Stress Response