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1. C16ORF70/MYTHO promotes healthy aging in C. elegans and prevents cellular senescence in mammals

Author

Franco-Romero, Anais, Morbidoni, Valeria, Milan, Giulia, Sartori, Roberta, Wulff, Jesper, Romanello, Vanina, Armani, Andrea, Salviati, Leonardo, Conte, Maria, Salvioli, Stefano, Franceschi, Claudio, Buonomo, Viviana, Swoboda, Casey O., Grumati, Paolo, Pannone, Luca, Martinelli, Simone, Jefferies, Harold B.J., Dikic, Ivan, van der Laan, Jennifer, Cabreiro, Filipe, Millay, Douglas P., Tooze, Sharon A., Trevisson, Eva, and Sandri, Marco

Subjects
Prevention, Physiological aspects, Analysis, Models, Genetic aspects, Caenorhabditis elegans -- Physiological aspects, Transcription (Genetics) -- Analysis, Cell aging -- Genetic aspects -- Prevention -- Models, Cells -- Aging, Genetic transcription -- Analysis
Abstract

Introduction In nature, organisms are continuously exposed to environmental stresses that challenge their survival. The species that quickly and efficiently adapt to hostile conditions are positively selected. This response is [...], The identification of genes that confer either extension of life span or accelerate age-related decline was a step forward in understanding the mechanisms of aging and revealed that it is partially controlled by genetics and transcriptional programs. Here, we discovered that the human DNA sequence C16ORF70 encodes a protein, named MYTHO (macroautophagy and youth optimizer), which controls life span and health span. MYTHO protein is conserved from Caenorhabditis elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the orthologous myt-1 gene in C. elegans dramatically shortened life span and decreased animal survival upon exposure to oxidative stress. Mechanistically, MYTHO is required for autophagy likely because it acts as a scaffold that binds WIPI2 and BCAS3 to recruit and assemble the conjugation system at the phagophore, the nascent autophagosome. We conclude that MYTHO is a transcriptionally regulated initiator of autophagy that is central in promoting stress resistance and healthy aging.

Published
2024
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3. Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence

Author

Tezze, Caterina, Romanello, Vanina, Desbats, Maria Andrea, Fadini, Gian Paolo, Albiero, Mattia, Favaro, Giulia, Ciciliot, Stefano, Soriano, Maria Eugenia, Morbidoni, Valeria, Cerqua, Cristina, Loefler, Stefan, Kern, Helmut, Franceschi, Claudio, Salvioli, Stefano, Conte, Maria, Blaauw, Bert, Zampieri, Sandra, Salviati, Leonardo, Scorrano, Luca, and Sandri, Marco

Published
2017
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4. Identification of a new COQ4 spliceogenic variant causing severe primary coenzyme Q deficiency

Author

Alcázar-Fabra, María, Østergaard, Elsebet, Fernández-Ayala, Daniel J.M., Desbats, María Andrea, Morbidoni, Valeria, Tomás-Gallado, Laura, García-Corzo, Laura, Blanquer-Roselló, María del Mar, Bartlett, Abigail K., Sánchez-Cuesta, Ana, Sena, Lucía, Cortés-Rodríguez, Ana, Cascajo-Almenara, María Victoria, Pagliarini, David J., Trevisson, Eva, Gronborg, Sabine W., and Brea-Calvo, Gloria

Published
2025
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5. Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet

Author

Rocchi, Anna, Milioto, Carmelo, Parodi, Sara, Armirotti, Andrea, Borgia, Doriana, Pellegrini, Matteo, Urciuolo, Anna, Molon, Sibilla, Morbidoni, Valeria, Marabita, Manuela, Romanello, Vanina, Gatto, Pamela, Blaauw, Bert, Bonaldo, Paolo, Sambataro, Fabio, Robins, Diane M., Lieberman, Andrew P., Sorarù, Gianni, Vergani, Lodovica, Sandri, Marco, and Pennuto, Maria

Published
2016
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6. Hybrid Minigene Assay: An Efficient Tool to Characterize mRNA Splicing Profiles of NF1 Variants

Author

Morbidoni, Valeria, primary, Baschiera, Elisa, additional, Forzan, Monica, additional, Fumini, Valentina, additional, Ali, Dario Seif, additional, Giorgi, Gianpietro, additional, Buson, Lisa, additional, Desbats, Maria Andrea, additional, Cassina, Matteo, additional, Clementi, Maurizio, additional, Salviati, Leonardo, additional, and Trevisson, Eva, additional

Published
2021
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7. Biallelic mutations in the TOGARAM1 gene cause a novel primary ciliopathy

Author

Morbidoni, Valeria, primary, Agolini, Emanuele, additional, Slep, Kevin C, additional, Pannone, Luca, additional, Zuccarello, Daniela, additional, Cassina, Matteo, additional, Grosso, Enrico, additional, Gai, Giorgia, additional, Salviati, Leonardo, additional, Dallapiccola, Bruno, additional, Novelli, Antonio, additional, Martinelli, Simone, additional, and Trevisson, Eva, additional

Published
2020
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9. Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells LackingCOQ6

Author

Acosta Lopez, Manuel J., primary, Trevisson, Eva, additional, Canton, Marcella, additional, Vazquez-Fonseca, Luis, additional, Morbidoni, Valeria, additional, Baschiera, Elisa, additional, Frasson, Chiara, additional, Pelosi, Ludovic, additional, Rascalou, Bérengère, additional, Desbats, Maria Andrea, additional, Alcázar-Fabra, María, additional, Ríos, José Julián, additional, Sánchez-García, Alicia, additional, Basso, Giuseppe, additional, Navas, Placido, additional, Pierrel, Fabien, additional, Brea-Calvo, Gloria, additional, and Salviati, Leonardo, additional

Published
2019
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10. DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass

Author

Favaro, Giulia, primary, Romanello, Vanina, additional, Varanita, Tatiana, additional, Andrea Desbats, Maria, additional, Morbidoni, Valeria, additional, Tezze, Caterina, additional, Albiero, Mattia, additional, Canato, Marta, additional, Gherardi, Gaia, additional, De Stefani, Diego, additional, Mammucari, Cristina, additional, Blaauw, Bert, additional, Boncompagni, Simona, additional, Protasi, Feliciano, additional, Reggiani, Carlo, additional, Scorrano, Luca, additional, Salviati, Leonardo, additional, and Sandri, Marco, additional

Published
2019
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12. Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance

Author

Gelli, Elisa, primary, Colombo, Mara, additional, Pinto, Anna, additional, De Vecchi, Giovanna, additional, Foglia, Claudia, additional, Amitrano, Sara, additional, Morbidoni, Valeria, additional, Imperatore, Valentina, additional, Manoukian, Siranoush, additional, Baldassarri, Margherita, additional, Lo Rizzo, Caterina, additional, Catania, Lorenza, additional, Frullanti, Elisa, additional, Tagliafico, Enrico, additional, Cortesi, Laura, additional, Spaggiari, Federica, additional, Mencarelli, Maria, additional, Trevisson, Eva, additional, Radice, Paolo, additional, Renieri, Alessandra, additional, and Ariani, Francesca, additional

Published
2019
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13. Biallelic mutations in the TOGARAM1 gene cause a novel primary ciliopathy.

Author

Morbidoni, Valeria, Agolini, Emanuele, Slep, Kevin C., Pannone, Luca, Zuccarello, Daniela, Cassina, Matteo, Grosso, Enrico, Gai, Giorgia, Salviati, Leonardo, Dallapiccola, Bruno, Novelli, Antonio, Martinelli, Simone, and Trevisson, Eva

Abstract

Background Dysfunction in non-motile cilia is associated with a broad spectrum of developmental disorders characterised by clinical heterogeneity. While over 100 genes have been associated with primary ciliopathies, with wide phenotypic overlap, some patients still lack a molecular diagnosis. Objective To investigate and functionally characterise the molecular cause of a malformation disorder observed in two sibling fetuses characterised by microphthalmia, cleft lip and palate, and brain anomalies. Methods A trio-based whole exome sequencing (WES) strategy was used to identify candidate variants in the TOGARAM1 gene. In silico, in vitro and in vivo (Caenorhabditis elegans) studies were carried out to explore the impact of mutations on protein structure and function, and relevant biological processes. Results TOGARAM1 encodes a member of the Crescerin1 family of proteins regulating microtubule dynamics. Its orthologue in C. elegans, che-12, is expressed in a subset of sensory neurons and localises in the dendritic cilium where it is required for chemosensation. Nematode lines harbouring the corresponding missense variant in TOGARAM1 were generated by CRISPR/Cas9 technology. Although chemotaxis ability on a NaCl gradient was not affected, che-12 point mutants displayed impaired lipophilic dye uptake, with shorter and altered cilia in sensory neurons. Finally, in vitro analysis of microtubule polymerisation in the presence of wild-type or mutant TOG2 domain revealed a faster polymerisation associated with the mutant protein, suggesting aberrant tubulin binding. Conclusions Our data are in favour of a causative role of TOGARAM1 variants in the pathogenesis of this novel disorder, connecting this gene with primary ciliopathy. [ABSTRACT FROM AUTHOR]

Published
2021
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14. Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6

Author

Fondazione Telethon, Istituto di Ricerca Pediatrica Città della Speranza, Fondation pour la Recherche Médicale, Agence Nationale de la Recherche (France), Instituto de Salud Carlos III, Junta de Andalucía, European Commission, Acosta-López, Manuel J., Trevisson, Eva, Canton, Marcella, Vázquez-Fonseca, Luis, Morbidoni, Valeria, Baschiera, Elisa, Frasson, Chiara, Ludovic, Pelosi, Rascalou, Bérengère, Desbats, María Andrea, Alcázar-Fabra, María, Ríos, José Julián, Sánchez-García, Alicia, Basso, Giuseppe, Navas, Plácido, Pierrel, Fabien, Brea-Calvo, Gloria, Salviati, Leonardo, Fondazione Telethon, Istituto di Ricerca Pediatrica Città della Speranza, Fondation pour la Recherche Médicale, Agence Nationale de la Recherche (France), Instituto de Salud Carlos III, Junta de Andalucía, European Commission, Acosta-López, Manuel J., Trevisson, Eva, Canton, Marcella, Vázquez-Fonseca, Luis, Morbidoni, Valeria, Baschiera, Elisa, Frasson, Chiara, Ludovic, Pelosi, Rascalou, Bérengère, Desbats, María Andrea, Alcázar-Fabra, María, Ríos, José Julián, Sánchez-García, Alicia, Basso, Giuseppe, Navas, Plácido, Pierrel, Fabien, Brea-Calvo, Gloria, and Salviati, Leonardo

Abstract

Coenzyme Q (CoQ), a redox-active lipid, is comprised of a quinone group and a polyisoprenoid tail. It is an electron carrier in the mitochondrial respiratory chain, a cofactor of other mitochondrial dehydrogenases, and an essential antioxidant. CoQ requires a large set of enzymes for its biosynthesis; mutations in genes encoding these proteins cause primary CoQ deficiency, a clinically and genetically heterogeneous group of diseases. Patients with CoQ deficiency often respond to oral CoQ10 supplementation. Treatment is however problematic because of the low bioavailability of CoQ10 and the poor tissue delivery. In recent years, bypass therapy using analogues of the precursor of the aromatic ring of CoQ has been proposed as a promising alternative. We have previously shown using a yeast model that vanillic acid (VA) can bypass mutations of COQ6, a monooxygenase required for the hydroxylation of the C5 carbon of the ring. In this work, we have generated a human cell line lacking functional COQ6 using CRISPR/Cas9 technology. We show that these cells cannot synthesize CoQ and display severe ATP deficiency. Treatment with VA can recover CoQ biosynthesis and ATP production. Moreover, these cells display increased ROS production, which is only partially corrected by exogenous CoQ, while VA restores ROS to normal levels. Furthermore, we show that these cells accumulate 3-decaprenyl-1,4-benzoquinone, suggesting that in mammals, the decarboxylation and C1 hydroxylation reactions occur before or independently of the C5 hydroxylation. Finally, we show that COQ6 isoform c (transcript NM_182480) does not encode an active enzyme. VA can be produced in the liver by the oxidation of vanillin, a nontoxic compound commonly used as a food additive, and crosses the blood-brain barrier. These characteristics make it a promising compound for the treatment of patients with CoQ deficiency due to COQ6 mutations.

Published
2019

15. Parent-of-origin effect of hypomorphic pathogenic variants and somatic mosaicism impact on phenotypic expression of retinoblastoma

Author

Imperatore, Valentina, primary, Pinto, Anna Maria, additional, Gelli, Elisa, additional, Trevisson, Eva, additional, Morbidoni, Valeria, additional, Frullanti, Elisa, additional, Hadjistilianou, Theodora, additional, De Francesco, Sonia, additional, Toti, Paolo, additional, Gusson, Elena, additional, Roversi, Gaia, additional, Accogli, Andrea, additional, Capra, Valeria, additional, Mencarelli, Maria Antonietta, additional, Renieri, Alessandra, additional, and Ariani, Francesca, additional

Published
2018
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16. Alport syndrome: impact of digenic inheritance in patients management

Author

Fallerini, C, Baldassarri, M, Trevisson, Eva, Morbidoni, Valeria, La Manna, A, Lazzarin, R, Pasini, A, Barbano, G, Pinciaroli, Ar, Garosi, G, Frullanti, E, Pinto, Am, Mencarelli, Ma, Mari, F, Renieri, A, and Ariani, F. .

Subjects
Adult, Collagen Type IV, Male, Multifactorial Inheritance, Alport syndrome, digenic inheritance, hypomorphic allele, massive parallel sequencing, hypomorphic allele, massive parallel sequencing, High-Throughput Nucleotide Sequencing, Genetic Counseling, Nephritis, Hereditary, Middle Aged, digenic inheritance, Autoantigens, Risk Assessment, Pedigree, Genes, X-Linked, Mutation, Humans, Female, Alport syndrome, Aged
Abstract

Alport syndrome (ATS) is a genetically heterogeneous nephropathy with considerable phenotypic variability and different transmission patterns, including monogenic (X-linked/autosomal) and digenic inheritance (DI). Here we present a new series of families with DI and we discuss the consequences for genetic counseling and risk assessment. Out of five families harboring variants in more than one COL4 gene detected by next generation sequencing (NGS), minigene-splicing assay allowed us to identify four as true digenic. Two families showed COL4A3/A4 mutations in cis, mimicking an autosomal dominant inheritance with a more severe phenotype and one showed COL4A3/A4 mutations in trans, mimicking an autosomal recessive inheritance with a less severe phenotype. In a fourth family, a de novo mutation (COL4A5) combined with an inherited mutation (COL4A3) triggered a more severe phenotype. A fifth family, predicted digenic on the basis of silico tools, rather showed monogenic X-linked inheritance due to a hypomorphic mutation, in accordance with a milder phenotype. In conclusion, this study highlights the impact of DI in ATS and explains the associated atypical presentations. More complex inheritance should be therefore considered when reviewing prognosis and recurrence risks. On the other side, these findings emphasize the importance to accompany NGS with splicing assays in order to avoid erroneous identification of at risk members.

Published
2016

17. Biallelic mutations in the TOGARAM1gene cause a novel primary ciliopathy

Author

Morbidoni, Valeria, Agolini, Emanuele, Slep, Kevin C, Pannone, Luca, Zuccarello, Daniela, Cassina, Matteo, Grosso, Enrico, Gai, Giorgia, Salviati, Leonardo, Dallapiccola, Bruno, Novelli, Antonio, Martinelli, Simone, and Trevisson, Eva

Abstract

BackgroundDysfunction in non-motile cilia is associated with a broad spectrum of developmental disorders characterised by clinical heterogeneity. While over 100 genes have been associated with primary ciliopathies, with wide phenotypic overlap, some patients still lack a molecular diagnosis.ObjectiveTo investigate and functionally characterise the molecular cause of a malformation disorder observed in two sibling fetuses characterised by microphthalmia, cleft lip and palate, and brain anomalies.MethodsA trio-based whole exome sequencing (WES) strategy was used to identify candidate variants in the TOGARAM1gene. In silico, in vitro and in vivo (Caenorhabditis elegans) studies were carried out to explore the impact of mutations on protein structure and function, and relevant biological processes.ResultsTOGARAM1encodes a member of the Crescerin1 family of proteins regulating microtubule dynamics. Its orthologue in C. elegans, che-12, is expressed in a subset of sensory neurons and localises in the dendritic cilium where it is required for chemosensation. Nematode lines harbouring the corresponding missense variant in TOGARAM1were generated by CRISPR/Cas9 technology. Although chemotaxis ability on a NaCl gradient was not affected, che-12point mutants displayed impaired lipophilic dye uptake, with shorter and altered cilia in sensory neurons. Finally, in vitro analysis of microtubule polymerisation in the presence of wild-type or mutant TOG2 domain revealed a faster polymerisation associated with the mutant protein, suggesting aberrant tubulin binding.ConclusionsOur data are in favour of a causative role of TOGARAM1variants in the pathogenesis of this novel disorder, connecting this gene with primary ciliopathy.

Published
2021
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18. The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction

Author

Salah, Heba, Li, Meishan, Cacciani, Nicola, Gastaldello, Stefano, Ogilvie, Hannah, Akkad, Hazem, Namuduri, Arvind Venkat, Morbidoni, Valeria, Artemenko, Konstantin A., Balogh, Gabor, Martinez-Redondo, Vicente, Jannig, Paulo, Hedström, Yvette, Dworkin, Barry, Bergquist, Jonas, Ruas, Jorge, Vigh, Laszlo, Salviati, Leonardo, Larsson, Lars, Salah, Heba, Li, Meishan, Cacciani, Nicola, Gastaldello, Stefano, Ogilvie, Hannah, Akkad, Hazem, Namuduri, Arvind Venkat, Morbidoni, Valeria, Artemenko, Konstantin A., Balogh, Gabor, Martinez-Redondo, Vicente, Jannig, Paulo, Hedström, Yvette, Dworkin, Barry, Bergquist, Jonas, Ruas, Jorge, Vigh, Laszlo, Salviati, Leonardo, and Larsson, Lars

Abstract

Ventilation-induced diaphragm dysfunction (VIDD) is a marked decline in diaphragm function in response to mechanical ventilation, which has negative consequences for individual patients' quality of life and for the health care system, but specific treatment strategies are still lacking. We used an experimental intensive care unit (ICU) model, allowing time-resolved studies of diaphragm structure and function in response to long-term mechanical ventilation and the effects of a pharmacological intervention (the chaperone co-inducer BGP-15). The marked loss of diaphragm muscle fiber function in response to mechanical ventilation was caused by post-translational modifications (PTMs) of myosin. In a rat model, 10 days of BGP-15 treatment greatly improved diaphragm muscle fiber function (by about 100%), although it did not reverse diaphragm atrophy. The treatment also provided protection from myosin PTMs associated with HSP72 induction and PARP-1 inhibition, resulting in improvement of mitochondrial function and content. Thus, BGP-15 may offer an intervention strategy for reducing VIDD in mechanically ventilated ICU patients.

Published
2016
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19. TheCOQ2genotype predicts the severity of coenzyme Q10deficiency

Author

Desbats, Maria Andrea, primary, Morbidoni, Valeria, additional, Silic-Benussi, Micol, additional, Doimo, Mara, additional, Ciminale, Vincenzo, additional, Cassina, Matteo, additional, Sacconi, Sabrina, additional, Hirano, Michio, additional, Basso, Giuseppe, additional, Pierrel, Fabien, additional, Navas, Placido, additional, Salviati, Leonardo, additional, and Trevisson, Eva, additional

Published
2016
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20. The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction

Author

Salah, Heba, primary, Li, Meishan, additional, Cacciani, Nicola, additional, Gastaldello, Stefano, additional, Ogilvie, Hannah, additional, Akkad, Hazem, additional, Namuduri, Arvind Venkat, additional, Morbidoni, Valeria, additional, Artemenko, Konstantin A., additional, Balogh, Gabor, additional, Martinez-Redondo, Vicente, additional, Jannig, Paulo, additional, Hedström, Yvette, additional, Dworkin, Barry, additional, Bergquist, Jonas, additional, Ruas, Jorge, additional, Vigh, Laszlo, additional, Salviati, Leonardo, additional, and Larsson, Lars, additional

Published
2016
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22. Collagen VI regulates satellite cell self-renewal and muscle regeneration

Author

Urciuolo, Anna, primary, Quarta, Marco, additional, Morbidoni, Valeria, additional, Gattazzo, Francesca, additional, Molon, Sibilla, additional, Grumati, Paolo, additional, Montemurro, Francesca, additional, Tedesco, Francesco Saverio, additional, Blaauw, Bert, additional, Cossu, Giulio, additional, Vozzi, Giovanni, additional, Rando, Thomas A., additional, and Bonaldo, Paolo, additional

Published
2013
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24. Collagen VI regulates satellite cell self-renewal and muscle regeneration

Author

Paolo Grumati, Paolo Bonaldo, Francesca Gattazzo, Giulio Cossu, Giovanni Vozzi, Anna Urciuolo, Francesca Montemurro, Marco Quarta, Sibilla Molon, Valeria Morbidoni, Francesco Tedesco, Bert Blaauw, Thomas A. Rando, Urciuolo, Anna, Quarta, Marco, Morbidoni, Valeria, Gattazzo, Francesca, Molon, Sibilla, Grumati, Paolo, Montemurro, Francesca, Tedesco, Francesco Saverio, Blaauw, Bert, Cossu, Giulio, Vozzi, Giovanni, Rando, Thomas A, and Bonaldo, Paolo

Subjects
Satellite Cells, Skeletal Muscle, Fluorescent Antibody Technique, General Physics and Astronomy, Collagen Type VI, In Vitro Techniques, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Extracellular matrix, Mice, 03 medical and health sciences, 0302 clinical medicine, Collagen VI, Elastic Modulus, Extracellular, medicine, Animals, Regeneration, Stem Cell Niche, Muscle, Skeletal, Cell Proliferation, 030304 developmental biology, Elastic Modulu, 0303 health sciences, Microscopy, Confocal, Multidisciplinary, Animal, In Vitro Technique, Cell growth, Regeneration (biology), Skeletal muscle, General Chemistry, Fibroblasts, biology.organism_classification, Cell biology, Mice, Inbred C57BL, medicine.anatomical_structure, Fibroblast, Satellite (biology), Stem cell, Extracellular Space, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Adult muscle stem cells, or satellite cells have essential roles in homeostasis and regeneration of skeletal muscles. Satellite cells are located within a niche that includes myofibers and extracellular matrix. The function of specific extracellular matrix molecules in regulating SCs is poorly understood. Here, we show that the extracellular matrix protein collagen VI is a key component of the satellite cell niche. Lack of collagen VI in Col6a1(-/-) mice causes impaired muscle regeneration and reduced satellite cell self-renewal capability after injury. Collagen VI null muscles display significant decrease of stiffness, which is able to compromise the in vitro and in vivo activity of wild-type satellite cells. When collagen VI is reinstated in vivo by grafting wild-type fibroblasts, the biomechanical properties of Col6a1(-/-) muscles are ameliorated and satellite cell defects rescued. Our findings establish a critical role for an extracellular matrix molecule in satellite cell self-renewal and open new venues for therapies of collagen VI-related muscle diseases.

Published
2013

25. The COQ2 genotype predicts the severity of coenzyme Q10 deficiency.

Author

Desbats MA, Morbidoni V, Silic-Benussi M, Doimo M, Ciminale V, Cassina M, Sacconi S, Hirano M, Basso G, Pierrel F, Navas P, Salviati L, and Trevisson E

Subjects
Alkyl and Aryl Transferases biosynthesis, Ataxia pathology, Gene Expression Regulation, Genotype, Humans, Mitochondria genetics, Mitochondria pathology, Mitochondrial Diseases pathology, Muscle Weakness pathology, Mutant Proteins biosynthesis, Mutation, Saccharomyces cerevisiae genetics, Severity of Illness Index, Ubiquinone genetics, Alkyl and Aryl Transferases genetics, Ataxia genetics, Mitochondrial Diseases genetics, Muscle Weakness genetics, Mutant Proteins genetics, Ubiquinone deficiency
Abstract

COQ2 (p-hydroxybenzoate polyprenyl transferase) encodes the enzyme required for the second step of the final reaction sequence of Coenzyme Q 10 (CoQ) biosynthesis. Its mutations represent a frequent cause of primary CoQ deficiency and have been associated with the widest clinical spectrum, ranging from fatal neonatal multisystemic disease to late-onset encephalopathy. However, the reasons of this variability are still unknown.We have characterized the structure of human COQ2, defined its subcellular localization and developed a yeast model to validate all the mutant alleles reported so far.Our findings show that the main functional transcript of COQ2 is shorter than what was previously reported and that its protein product localizes to mitochondria with the C-terminus facing the intermembrane space. Complementation experiments in yeast showed that the residual activity of the mutant proteins correlates with the clinical phenotypes observed in patients.We defined the structure of COQ2 with relevant implications for mutation screening in patients and demonstrated that, contrary to other COQ gene defects such as ADCK3, there is a correlation between COQ2 genotype and patient's phenotype., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2016
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