Consorzio MitMed: dall’identificazione e caratterizzazione di geni nucleari responsabili di malattie mitocondriali verso potenziali approcci terapeutici in modelli sperimentali
- 3.5 Anni 2015/2019
- 361.357€ Totale Fondi
Il mitocondrio è un organello cellulare che svolge la funzione di centrale energetica della cellula e possiede un proprio DNA (DNA mitocondriale o mtDNA) diverso da quello contenuto nel nucleo. Le malattie mitocondriali (MM) possono essere causate sia da mutazioni del mtDNA sia da mutazioni del DNA nucleare. Questa ampia eterogeneità risulta problematica non solo per identificare nuovi geni malattia, ma anche per diagnosticare il difetto genetico in una MM, visto che è difficile testare tutti i diversi geni noti. In questo progetto (MitMed) useremo il sequenziamento di nuova generazione (NGS), una tecnica che permette di leggere contemporaneamente la sequenza della porzione più informativa del DNA (esoma), al fine di identificare nuovi geni malattia e migliorare la diagnosi genetica in pazienti con MM. Nel nostro precedente progetto (GPP11011) abbiamo già identificato, sempre tramite NGS, due mutazioni in geni fino ad ora non associati a MM. Il prossimo passo sarà studiare con test in vitro le proteine corrispondenti ai geni mutati identificati mediante l’NGS.. Le mutazioni identificate ed eventuali nuove mutazioni verranno studiate anche in organismi modello di lievito, mosca e pesce, che riproducono le mutazioni umane in alcuni geni tra cui MPV17 e APOPT1, gene in cui abbiamo recentemente identificato mutazioni che causano leucoencefalopatia mitocondriale. Ulteriori geni verranno studiati allo scopo di comprendere i meccanismi d’azione che portano all’insorgenza di MM. Mediante l’utilizzo di un modello di lievito che riproduce la mutazione nel gene POLG, studi preliminari ci hanno già permesso di identificare 6 molecole, che verranno testate utilizzando i modelli sperimentali disponibili. Obiettivo di questo progetto è sfruttare le conoscenze acquisite negli scorsi anni sia per migliorare la diagnosi genetica nei pazienti, sia per testare nuovi potenziali farmaci
Pubblicazioni Scientifiche
- 2016-06-02 AMERICAN JOURNAL OF HUMAN GENETICS
Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency
- 2016-10-06 AMERICAN JOURNAL OF HUMAN GENETICS
Recurrent De Novo Dominant Mutations in SLC2SA4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number
- 2019-05-01 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Homozygous variant in OTX2 and possible genetic modifiers identified in a patient with combined pituitary hormone deficiency, ocular involvement, myopathy, ataxia, and mitochondrial impairment
- 2020-07-01 ANNALS OF NEUROLOGY
ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy
- 2017-11-18 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Dominance of yeast aac2R96H and aac2R252G mutations, equivalent to pathological mutations in ant1, is due to gain of function
- 2021-01-19 CELL DEATH & DISEASE
Efficient clofilium tosylate-mediated rescue of POLG-related disease phenotypes in zebrafish
- 2019-03-01 DISEASE MODELS & MECHANISMS
The zebrafish orthologue of the human hepatocerebral disease gene MPV17 plays pleiotropic roles in mitochondria
- 2019-07-01 EUROPEAN JOURNAL OF HUMAN GENETICS
Biallelic missense and deep intronic NDUFAF6 variants, unraveled by exome sequencing and mRNA analysis, in patients with Leigh syndrome
- 2018-12-07 FRONTIERS IN GENETICS
Clinical and Biochemical Features in a Patient With Mitochondrial Fission Factor Gene Alteration
- 2018-11-30 HAEMATOLOGICA
Sideroblastic anemia with myopathy secondary to novel, pathogenic missense variants in the YARS2 gene
- 2024-08-15 HELIYON
Long-term effects of daylight saving time on driving fatigue
- 2017-11-01 HUMAN MOLECULAR GENETICS
Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome
- 2019-11-15 HUMAN MOLECULAR GENETICS
Molecular genetic investigations identify new clinical phenotypes associated with BCS1L-related mitochondrial disease
- 2017-08-01 HUMAN MUTATION
Recessive mutations in MSTO1 cause mitochondrial dynamics impairment, leading to myopathy and ataxia
- 2018-04-01 HUMAN MUTATION
Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease
- 2019-05-01 HUMAN MUTATION
Clinical-genetic features and peculiar muscle histopathology in infantile DNM1L-related mitochondrial epileptic encephalopathy
- 2019-10-01 HUMAN MUTATION
Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3′-end processing
- 2021-01-01 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Exploring Yeast as a Study Model of Pantothenate Kinase-Associated Neurodegeneration and for the Identification of Therapeutic Compounds
- 2021-05-01 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
A Yeast-Based Screening Unravels Potential Therapeutic Molecules for Mitochondrial Diseases Associated with Dominant ANT1 Mutations
- 2021-11-01 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool
- 2023-10-20 ISCIENCE
Drosophila Mpv17 forms an ion channel and regulates energy metabolism
- 2017-06-01 JAMA NEUROLOGY
Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy
- 2018-01-01 JAMA NEUROLOGY
Neurologic Phenotypes Associated With Mutations in RTN4IP1 (OPA10) in Children and Young Adults
- 2018-05-01 JOURNAL OF HUMAN GENETICS
Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis
- 2019-03-01 JOURNAL OF INHERITED METABOLIC DISEASE
Clinical, radiological, and genetic characteristics of 16 patients with ACO2 gene defects: Delineation of an emerging neurometabolic syndrome
- 2016-12-01 JOURNAL OF MEDICAL GENETICS
COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency
- 2017-12-01 JOURNAL OF MEDICAL GENETICS
A novel de novo dominant mutation in ISCU associated with mitochondrial myopathy
- 2019-11-01 JOURNAL OF MOLECULAR MEDICINE-JMM
A combination of two novel VARS2 variants causes a mitochondrial disorder associated with failure to thrive and pulmonary hypertension
- 2019-11-01 MITOCHONDRION
Amino and carboxy-terminal extensions of yeast mitochondrial DNA polymerase assemble both the polymerization and exonuclease active sites
- 2019-06-01 MOLECULAR GENETICS & GENOMIC MEDICINE
Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy
- 2019-08-01 MUSCLE & NERVE
New missense variants of NDUFA11 associated with late-onset myopathy
- 2018-10-03 NATURE COMMUNICATIONS
Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder
- 2020-07-01 NEUROBIOLOGY OF DISEASE
A homozygous MRPL24 mutation causes a complex movement disorder and affects the mitoribosome assembly
- 2019-09-01 NEUROLOGICAL SCIENCES
DNMT1-complex disorder caused by a novel mutation associated with an overlapping phenotype of autosomal-dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) and hereditary sensory neuropathy with dementia and hearing loss (HSN1E)
- 2017-05-12 ORPHANET JOURNAL OF RARE DISEASES
Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations
- 2018-04-04 ORPHANET JOURNAL OF RARE DISEASES
KARS-related diseases: progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature
- 2018-10-01 PLOS ONE
Pathological alleles of MPV17 modeled in the yeast Saccharomyces cerevisiae orthologous gene SYM1 reveal their inability to take part in a high molecular weight complex
- 2024-10-01 TRANSPORTATION RESEARCH PART F-TRAFFIC PSYCHOLOGY AND BEHAVIOUR
Corrigendum to "Driving fatigue increases after the spring transition to daylight saving time in young male drivers: A pilot study" [Transport. Res. Part F: Traffic Psychol. Behav. 99 (2023) 83-97]
