title: Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor.
abstract: 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.
authors.affiliation: Division of Molecular Neurogenetics, The Carlo Besta Neurological Institute Foundation, Istituto di Ricovero e Cura a Carattere Scientifico, via Temolo 4, 20126, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
authors.forename: Irina
authors.initials: I
authors.lastname: Sevrioukova
authors.forename: Federica
authors.initials: F
authors.lastname: Invernizzi
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
authors.forename: Pio
authors.initials: P
authors.lastname: D'Adamo
authors.forename: Francesca
authors.initials: F
authors.lastname: Novara
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.forename: Graziella
authors.initials: G
authors.lastname: Uziel
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
mesh_terms: D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000235:genetics* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003198:Computer Simulation; D017931:DNA Primers / Q000737:chemistry; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D019587:Dietary Supplements; D004579:Electron Transport / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D050172:Genes, X-Linked; D006801:Humans; D020287:In Situ Nick-End Labeling; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009422:Nervous System Diseases / Q000188:drug therapy / Q000209:etiology; D010375:Pedigree; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011487:Protein Conformation; D012256:Riboflavin / Q000008:administration & dosage; D019311:Staurosporine / Q000494:pharmacology; D014430:Twins, Monozygotic
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D017931:DNA Primers; D004272:DNA, Mitochondrial; D005182:Flavin-Adenine Dinucleotide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D019311:Staurosporine; D012256:Riboflavin