Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor.

TitleSevere X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor.
Publication TypeJournal Article
Year of Publication2010
AuthorsGhezzi, D, Sevrioukova, I, Invernizzi, F, Lamperti, C, Mora, M, D'Adamo, P, Novara, F, Zuffardi, O, Uziel, G, Zeviani, M
JournalAm J Hum Genet
Date Published2010 Apr 09
KeywordsApoptosis, Apoptosis Inducing Factor, Caspase 3, Computer Simulation, Dietary Supplements, DNA Primers, DNA, Mitochondrial, Electron Transport, Female, Fibroblasts, Flavin-Adenine Dinucleotide, Genes, X-Linked, Humans, In Situ Nick-End Labeling, Infant, Newborn, Magnetic Resonance Imaging, Male, Mitochondrial Encephalomyopathies, Muscle, Skeletal, Mutation, Nervous System Diseases, Pedigree, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases, Protein Conformation, Riboflavin, Staurosporine, Twins, Monozygotic

We investigated two male infant patients who were given a diagnosis of progressive mitochondrial encephalomyopathy on the basis of clinical, biochemical, and morphological features. These patients were born from monozygotic twin sisters and unrelated fathers, suggesting an X-linked trait. Fibroblasts from both showed reduction of respiratory chain (RC) cIII and cIV, but not of cI activities. We found a disease-segregating mutation in the X-linked AIFM1 gene, encoding the Apoptosis-Inducing Factor (AIF) mitochondrion-associated 1 precursor that deletes arginine 201 (R201 del). Under normal conditions, mature AIF is a FAD-dependent NADH oxidase of unknown function and is targeted to the mitochondrial intermembrane space (this form is called AIF(mit)). Upon apoptogenic stimuli, a soluble form (AIF(sol)) is released by proteolytic cleavage and migrates to the nucleus, where it induces "parthanatos," i.e., caspase-independent fragmentation of chromosomal DNA. In vitro, the AIF(R201 del) mutation decreases stability of both AIF(mit) and AIF(sol) and increases the AIF(sol) DNA binding affinity, a prerequisite for nuclear apoptosis. In AIF(R201 del) fibroblasts, staurosporine-induced parthanatos was markedly increased, whereas re-expression of AIF(wt) induced recovery of RC activities. Numerous TUNEL-positive, caspase 3-negative nuclei were visualized in patient #1's muscle, again indicating markedly increased parthanatos in the AIF(R201 del) critical tissues. We conclude that AIF(R201 del) is an unstable mutant variant associated with increased parthanatos-linked cell death. Our data suggest a role for AIF in RC integrity and mtDNA maintenance, at least in some tissues. Interestingly, riboflavin supplementation was associated with prolonged improvement of patient #1's neurological conditions, as well as correction of RC defects in mutant fibroblasts, suggesting that stabilization of the FAD binding in AIF(mit) is beneficial.

Alternate JournalAm. J. Hum. Genet.
Citation Key10.1016/j.ajhg.2010.03.002
PubMed ID20362274
PubMed Central IDPMC2850437
Grant ListGGP07019 / / Telethon / Italy