Deleterious mutations in ALDH1L2 suggest a novel cause for neuro-ichthyotic syndrome

Abstract

Neuro-ichthyotic syndromes are a group of rare genetic diseases mainly associated with perturbations in lipid metabolism, intracellular vesicle trafficking, or glycoprotein synthesis. Here, we report a patient with a neuro-ichthyotic syndrome associated with deleterious mutations in the ALDH1L2 (aldehyde dehydrogenase 1 family member L2) gene encoding for mitochondrial 10-formyltetrahydrofolate dehydrogenase. Using fibroblast culture established from the ALDH1L2-deficient patient, we demonstrated that the enzyme loss impaired mitochondrial function affecting both mitochondrial morphology and the pool of metabolites relevant to β-oxidation of fatty acids. Cells lacking the enzyme had distorted mitochondria, accumulated acylcarnitine derivatives and Krebs cycle intermediates, and had lower ATP and increased ADP/AMP indicative of a low energy index. Re-expression of functional ALDH1L2 enzyme in deficient cells restored the mitochondrial morphology and the metabolic profile of fibroblasts from healthy individuals. Our study underscores the role of ALDH1L2 in the maintenance of mitochondrial integrity and energy balance of the cell, and suggests the loss of the enzyme as the cause of neuro-cutaneous disease.

Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial folate enzyme to deregulation of a lipid metabolism observed in rare human disorder

“…2 a). The changes in 10-formyl-THF agree with the role of ALDH1L2-catalyzed reaction and correspond to the elevation of this folate pool in a patient lacking ALDH1L2 expression due to compound heterozygous mutations [ 5 ].

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“…The analysis was carried out essentially as described [ 5 , 20 – 22 ]. Two types of statistical analyses were performed: (1) significance tests and (2) classification analysis.…”

“…While the biological significance of this enzyme is not fully understood, it was reported that the ALDH1L2-catalyzed reaction is an important source of NADPH in mitochondria [ 3 ], and this function links the enzyme to melanoma metastasis [ 4 ]. We have recently reported that the loss of the ALDH1L2 activity through deleterious mutations in the ALDH1L2 gene is linked to neuro-ichthyotic syndrome [ 5 ]. Such syndromes represent a group of rare genetic diseases commonly associated with impaired lipid metabolism [ 6 ].…”

“…One of the most recognized of these conditions, Sjögren–Larsson syndrome (SLS: MIM#270200), is typically caused by mutations in the ALDH3A2 gene encoding for fatty acid aldehyde dehydrogenase and characterized by congenital ichthyosis, leukoencephalopathy, intellectual disability, and spastic di- or tetraplegia [ 7 ]. ALDH1L2-deficient patient displayed atypical phenotype with fibroblasts derived from his skin showing strong changes in acylcarnitines and intermediates of the Krebs cycle compared to the cells from healthy individuals [ 5 ]. Overall, this study demonstrated that ALDH1L2 is important for the mitochondrial integrity and for maintenance of the energy balance in the cell.…”

Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance

“…The cytosolic counterpart of ALDH1L2, ALDH1L1 is expressed abundantly in astrocytes (Neymeyer et al, 1997;Foo and Dougherty, 2013). ALDH1L2 mutations seem to induce astrocytic stress (Sarret et al, 2019). Interestingly, complex I deficiency has been shown to decrease NADPH synthesis via ALDH1L2 due to the impaired generation of NAD + (Balsa et al, 2020).…”