دورية أكاديمية
Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor.
| العنوان: | Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor. |
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| المؤلفون: | D. Ghezzi, I. Sevrioukova, F. Invernizzi, C. Lamperti, M. Mora, F. Novara, O. Zuffardi, G. Uziel, M. Zeviani, D'ADAMO, ADAMO PIO |
| المساهمون: | D., Ghezzi, I., Sevrioukova, F., Invernizzi, C., Lamperti, M., Mora, D'Adamo, ADAMO PIO, F., Novara, O., Zuffardi, G., Uziel, M., Zeviani |
| سنة النشر: | 2010 |
| المجموعة: | Università degli studi di Trieste: ArTS (Archivio della ricerca di Trieste) |
| مصطلحات موضوعية: | Apoptosi, Apoptosis Inducing Factor, Apoptosis Inducing Factor: genetic, Apoptosis Inducing Factor: metabolism, Caspase 3, Caspase 3: metabolism, Computer Simulation, DNA, DNA Primer, DNA Primers: chemistry, Dietary Supplement, Electron Transport, Electron Transport: physiology, Female, Fibroblast, Fibroblasts: cytology, Fibroblasts: drug effect, Fibroblasts: metabolism, Flavin-Adenine Dinucleotide, Flavin-Adenine Dinucleotide: metabolism, Gene, Human, In Situ Nick-End Labeling, Infant, Magnetic Resonance Imaging, Male, Mitochondrial, Mitochondrial Encephalomyopathie, Mitochondrial Encephalomyopathies: genetic, Mitochondrial Encephalomyopathies: metabolism |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | STAMPA |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/20362274; info:eu-repo/semantics/altIdentifier/wos/WOS:000276716800016; volume:86; firstpage:639; lastpage:649; numberofpages:11; journal:AMERICAN JOURNAL OF HUMAN GENETICS; http://hdl.handle.net/11368/2489177Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-77950326171; http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2850437Test\&tool=pmcentrez\&rendertype=abstract |
| DOI: | 10.1016/j.ajhg.2010.03.002 |
| الإتاحة: | https://doi.org/10.1016/j.ajhg.2010.03.002Test http://hdl.handle.net/11368/2489177Test http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2850437Test\&tool=pmcentrez\&rendertype=abstract |
| رقم الانضمام: | edsbas.DF217430 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.ajhg.2010.03.002 |
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