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Timestamp: 2019-04-24 22:33:07+00:00

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Despite the majority of mitochondrial respiratory chain (MRC) components are nuclear-encoded, each mitochondrion contains 2 to 10 copies of a small (16569bp), circular, double-stranded DNA molecule. Mitochondrial diseases can be secondary to mutations either in the mitochondrial or in the nuclear genome and are responsible for a large variety of clinical syndromes. In the team, we are studying mitochondrial disorders and mainly those associated with mtDNA instability. We have shown that the origin of the instability may be exceptionally dependent on mtDNA itself by describing, for the first time, an unstable mutation in a mitochondrial gene encoding a complex I subunit (MT-ND6), which is responsible for Maternally Inherited Diabetes and Deafness (MIDD) (Bannwarth et al., 2011). Nevertheless, in most cases, human diseases associated with loss of mtDNA copies (depletion) or accumulation of multiple mtDNA deletions have an autosomal mode of inheritance, indicating that a defect in a nuclear gene is responsible for mtDNA instability. Indeed, the factors involved in mtDNA maintenance are encoded by nuclear genes and imported into mitochondria. Mutations in any of these genes may disturb mtDNA maintenance mechanisms and cause either quantitative or qualitative mtDNA molecular lesions. A few number of defective genes has been identified but, in most patients, genes and molecular mechanisms responsible for mtDNA alterations remain unknown.
From Aleksandra Trifunovic et al.
A-B. Histopathology with Gomori modified trichrome (A) showing RRFs and COX/SDH stain (B) revealing COX-deficient fibres, which are recognized by the prevalent blue stain.
C. Ultrastructure of skeletal muscle showing accumulation of lipid droplets and abnormal enlarged mitochondria with paracristallin inclusions. Original magnification: x12000.
the connectivity of the mitochondrial network.
A. Control individual. B. Patient. From Rouzier et al., Brain, 2012.
This work is made in direct collaboration with the Department of Medical Genetics and the Reference Centre for Mitochondrial Diseases (CHU of Nice, Archet 2 hospital), both managed by Véronique Paquis-Flucklinger. In this Centre, we collected a large series of patients with MRC defects. This situation allows a direct link between basic and medical research. The research team benefits from the collection of patients and the expertise of referring clinicians. The recent identification of MFN2, involved in the mitochondrial fusion, as a new gene associated with "mtDNA breakage syndrome" (Rouzier et al., 2012), illustrates the value of this collaboration.
This is another approach used in the laboratory. For example, we are currently studying a protein involved in mtDNA metabolism through the analysis of KO mice. The animals developed a mitochondrial myopathy after 1 year of age with respiratory chain deficiency and accumulation of mtDNA deletions. KO mice exhibited a significantly lower daily running distance compared to wild-type animals, indicating muscle weakness. We find that the mitochondrial isoform encoded by this gene, generated via downstream alternative translation initiation (dATI), was present inside mitochondria and bound to mtDNA in vivo. Furthermore, gene inactivation caused a deficiency in repair of oxidative mitochondrial DNA damage, thus confirming the role of this protein in mtDNA maintenance. These results open new avenues for the exploration of patients with mtDNA instability disorders and for the study of thid protein that plays a critical role in the maintenance of mtDNA stability, possibly preventing age-associated accumulation of mtDNA mutations.
Belmonte F, Michiels JF, Ricci JE, Gherardi R, Harrington L, Kaufman BA, Paquis-Flucklinger V.
Inactivation of Pif1 helicase causes a mitochondrial myopathy in mice.
Mitochondrion 2016 Feb 23 pii: S1567-7249(16)30008-3.
Fragaki, Chaussenot A, Benoist JF, Ait-El-Mkadem S, Bannwarth S, Rouzier C, Cochaud C, Paquis-Flucklinger V.
Coenzyme Q10 defects may be associated with a deficiency of Q10-independent mitochondrial respiratory chain complexes.
Biol Res 2016; Jan 8;49(1):4.
Auge G, Moore D, Burte F, Lacas-Gervais S, Kageyama Y, Itoh K, Yu-Wai-Man P, Sesaki H, Ricci JE, Vives-Bauza C, Paquis-Flucklinger V.
CHCHD10 mutations promote loss of mitochondrial cristae junctions with defect in mitochondrial genome maintenance and apoptosis.
EMBO Mol Med 2015 ; Dec 14;8(1):58-72 (Citation core facility PICMI IRCAN).
Brain 2015 ; Dec 30. pii: awv368.
Ait-El-Mkadem S, Chaussenot A, Bannwarth S, Paquis-Flucklinger V.
CHCHD10-Related Disorders. 2015 Jul In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet].
Dayem-Quere M, Giuliano F, Massol C, Piche M, Paquis-Flucklinger V, Karmous-Benailly H.
De novo 4q duplication/deletion in a fetus with a congenital heart defect.
Am J Med Genet A 2015; Aug;167A(8):1932-6.
frontotemporal dementia and amyotrophic lateral sclerosis?
kindred with motor neuron disease carrying a CHCHD10 mutation.
Brice A, Yu Wai Man P, Sesaki H, Pouget J, Paquis-Flucklinger V. Reply: CHCHD10 mutations in Italian sporadic ALS patients.
Plutino M, Chaussenot A, Ait-El-Mkadem S, Bannwarth S, Genin EC, Rouzier C, Augé G, Sacconi S, Pouget J, Paquis-Flucklinger V.
significant cause of late-onset cerebellar ataxia syndrome.
J Neurol Sci 2014; 347:322-324.
Yu Wai Man P, Sesaki H, Pouget J, Paquis-Flucklinger V.
Reply: Are CHCHD10 mutations indeed associated with familial amyotrophic lateral sclerosis ?
Brice A, Yu Wai Man P, Sesaki H, Pouget J, Paquis-Flucklinger V.
Reply: Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis.
Reply: Two novel mutations in conserved codons indicate that CHCHD10 is a motor neuron disease gene.
The French research network on FTD and FTD-ALS, Brice A, Pouget J, Paquis-Flucklinger V.
Brice A, Yu Wai Man P, Sesaki H, Pouget J, Paquis-Flucklinger V. *Equal participation.
Chabrol B, Vialettes B, Paquis-Flucklinger V.
Mutation update and uncommon phenotypes in a French cohort of 96 patients with WFS1-related disorders.
An overview of neurological and neuromucular signs in mitochondrial diseases.
Rohayem J, Sinnott R, Tillmann V, Tranebjaerg L, Barrett TG.
EURO-WABB: an EU rare diseases registry for Wolfram syndrome, Alström syndrome and Bardet-Biedl syndrome.
BMC Pediatr 2013; Aug 27;13:130.
Le Quan Sang KH, Amati-Bonneau P, Falk MJ, Florentz C, Chabrol B, Durand-Zaleski I, Paquis-Flucklinger V.
Sacconi S, Mousson de Camaret B, Rio M, Lebre AS, Jardel C, Deschamps R, Richelme C, Pouget J, Chabrol B, Paquis-Flucklinger V.
Interest of QMPSF analysis in the detection of large intragenic POLG1 rearrangements through the study of a large French cohort.
Ribière C, Kaboré FA, Chaussenot A, Paquis-Flucklinger V, Lenne-Aurier K, Gaillet S, Boissier R, Karsenty G.
Bladder-sphincter disorders associated with Wolfram syndrome.
Procaccio V, Rötig A, Paquis-Flucklinger V. *Equal participation.
Eur J Hum Genet 2013; 21:528-34.
Rötig A, Michiels JF, Vande Velde C, Paquis-Flucklinger V.
mitochondria and protects the mitochondrial genome from oxidative damage.
Epilepsy and mitochondrial diseases : retrospective study on 53 epileptic children.
Pellissier JF, Procaccio V, Chabrol B, Paquis-Flucklinger V.
The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy ‘plus’ phenotype.
Lévy N, Chiaroni J, Paquis-Flucklinger V, Fellmann F, Mitchell MJ.
HSFY genes and the P4 palindrome in the AZFb interval of the human Y chromosome are not required for spermatocyte maturation.
Titah SM, Meunier I, Blanchet C, Lopez S, Rondouin G, Lenaers G, Amati-Bonneau P, Reynier P, Paquis-Flucklinger V, Hamel CP.
Cataract as a phenotypic marker for a mutation in WFS1, the Wolfram syndrome gene.
Eur J Ophthalmol 2012; 22:254-8.
Bannwarth S, Abbassi M, Valéro R, Fragaki, K, Dubois N, Vialettes B, Paquis-Flucklinger V.
A novel unstable mutation in mitochondrial DNA responsible for maternally inherited diabetes and deafness.
Fragaki K, Cano A, Chaussenot A, Rouzier C, Bannwarth S, Caruba C, Chabrol B, Paquis-Flucklinger V.
Fatal heart failure associated with coenzyme Q10 OXPHOS deficiency in an infant with propionic academia.
Chaussenot A, Bannwarth S, Rouzier C, Vialettes B, Ait El Mkadem S, Chabrol B, Cano A, Labauge P, Paquis-Flucklinger V.
Neurologic features and genotype-phenotype correlation in Wolfram syndrome.
Annals Neurol 2011; 69 : 501-8.
Valayannopoulos V, de Lonlay P, Desguerre I, Brunelle F, Bonnefont JP, Rötig A, Munnich A, Boddaert N.
A common pattern of brain MRI imaging in mitochondrial diseases with complex I deficiency.
J Med Genet 2011; 48:16-23.
Paquis-Flucklinger V, Virolle T. EGFR immunolabeling pattern may discriminate low-grade gliomas from gliosis.
Ninove L, Daniel L, Gallou J, Cougard PA, Charpentier A, Viard L, Roquelaure B, Paquis-Flucklinger V, de Lamballerie X, Zandotti C, Charrel RN.
Fatal case of Reye's syndrome associated with H3N2 influenza virus infection and salicylate intake in a 12-year-old patient.
Clin Microbiol Infect 2011; 17:95-7.
Rouzier C, Le Guédard-Méreuze S, Fragaki K, Serre V, Miro J, S. Tuffery-Giraud, A. Chaussenot, S. Bannwarth, C.
Caruba, E. Ostergaard, J.F. Pellissier, C. Richelme, C. Espil, B. Chabrol, Paquis-Flucklinger V.
J Med Genet 2010; 47:670-676.
Labauge P, Renard D, Chaussenot A, Paquis-Flucklinger V.
Neurological picture.Wolfram syndrome associated with leukoencephalopathy.
J Neurol Neurosurg Psychiatry 2010; 81:928.
Lahaye F, Lespinasse F, Staccini P, Palin L, Paquis-Flucklinger V, Santucci-Darmanin S.
hMSH5 is a nucleocytoplasmic shuttling protein whose stability depends on its subcellular localization.
Nucleic Acids Res 2010; 38:3655-71.
Paquis-Flucklinger V, Harigaya Y, Ibi T, Goto Y, Hosoya H, DiMauro S, Hirano M, Tanaka M.
Extensive screening system using suspension array technology to detect mitochondrial DNA point mutations.
Fromont I, Nicoli F, Valéro R, Felician O, Lebail B, Lefur Y, Mancini J, Paquis-Flucklinger, V., Cozzone PJ, Vialettes B. Brain anomalies in maternally inherited diabetes and deafness syndrome. J Neurol, 256:1696-704 (2009).
Bannwarth S, Procaccio V, Paquis-Flucklinger, V. Rapid identification of unknown heteroplasmic mitochondrial DNA mutations with mismatch-specific surveyor nuclease. Methods Mol Biol, 554:301-13 (2009).
Laloi-Michelin M, Meas T, Ambonville C, Bellanné-Chantelot C, Beaufils S, Massin P, Vialettes B, Gin H, Timsit J, Bauduceau B, Bernard L, Bertin E, Blickle JF, Cahen-Varsaux J, Cailleba A, Casanova S, Cathebras P, Charpentier G, Chedin P, Crea T, Delemer B, Dubois-Laforgue D, Duchemin F, Ducluzeau PH, Bouhanick B, Dusselier L, Gabreau T, Grimaldi A, Guerci B, Jacquin V, Kaloustian E, Larger E, Lecleire-Collet A, Lorenzini F, Louis J, Mausset J, Murat A, Nadler-Fluteau S, Olivier F, Paquis-Flucklinger, V., Paris-Bockel D, Raynaud I, Reznik Y, Riveline JP, Schneebeli S, Sonnet E, Sola-Gazagnes A, Thomas JL, Trabulsi B, Virally M, Guillausseau PJ; Mitochondrial Diabetes French Study Group. The clinical variability of maternally inherited diabetes and deafness is associated with the degree of heteroplasmy in blood leukocytes. J Clin Endocrinol Metab, 94:3025-30 (2009).
Massin P, Dubois-Laforgue D, Meas T, Laloi-Michelin M, Gin H, Bauduceau B, Bellanné-Chantelot C, Bertin E, Blickle JF, Bouhanick B, Cahen-Varsaux J, Casanova S, Charpentier G, Chedin P, Dupuy O, Grimaldi A, Guerci B, Kaloustian E, Lecleire-Collet A, Lorenzini F, Murat A, Narbonne H, Olivier F, Paquis-Flucklinger, V., Virally M, Vincenot M, Vialettes B, Timsit J, Guillausseau PJ; for the GEDIAM (Mitochondrial Diabetes French Study Group). Retinal and renal complications in patients with a mutation of mitochondrial DNA at position 3,243 (maternally inherited diabetes and deafness). A case-control study. Diabetologia, 51:1664-1670 (2008).
Valéro R, Bannwarth S, Roman S, Paquis-Flucklinger, V., Vialettes B. Autosomal dominant transmission of diabetes and congenital hearing impairment secondary to a missense mutation in the WFS1 gene. Diabet Med, 25:657-61 (2008).
Neyton S, Lespinasse F, Lahaye F, Staccini P, Paquis-Flucklinger, V., Santucci-Darmanin S. CRM1-dependent nuclear export and dimerization with hMSH5 contribute to the regulation of hMSH4 subcellular localization. Exp Cell Res, 313: 3680-93 (2007).
Bourdon A, Minai L, Serre V, Jais JP, Sarzi E, Aubert S, Chrétien D, de Lonlay P, Paquis-Flucklinger, V., Arakawa H, Nakamura Y, Munnich A, Rôtig A. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet, 39 : 776-780 (2007).
Cano A, Molines L, Valéro R, Simonin G, Paquis-Flucklinger, V., Vialettes B; French Group of Wolfram Syndrome. Microvascular diabetes complications in Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness [DIDMOAD]): an age- and duration-matched comparison with common type 1 diabetes. Diabetes Care, 30 : 2327-30 (2007).
Cano A, Rouzier C, Monnot S, Chabrol B, Conrath J, Lecomte P, Delobel B, Boileau P, Valero R, Procaccio V, Paquis-Flucklinger, V.; French Group of Wolfram Syndrome, Vialettes B. Identification of novel mutations in WFS1 and genotype-phenotype correlation in Wolfram syndrome. Am J Med Genet A, 143A(14):1605-12 (2007).
Naïmi M, Bannwarth S, Procaccio V, Pouget J, Desnuelle C, Pellissier JF, Rötig A, Munnich A, Calvas P, Richelme C, Jonveaux P, Castelnovo G, Simon M, Clanet M, Wallace D, Paquis-Flucklinger, V. Molecular analysis of ANT1, Twinkle and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay. Eur J Hum Genet, 14, 917-922 (2006).
Bouchet C, Steffan J, Corcos J, Monnot S, Paquis-Flucklinger, V., Rotig A, Lebon S, Levy P, Royer G, Giurgea I, Gigarel N, Benachi A, Dumez Y, Munnich A, Bonnefond JP. Prenatal diagnosis of MELAS syndrome : contribution to understanding mitochondrial DNA segregation during human embryo fœtal development. J Med Genet. 11 (2006).
Procaccio V, Neckelmann N, Paquis-Flucklinger, V., Bannwarth S., Jimenez R, Davila A, Poole JC, Wallace DC. Detection of low levels of the 3243A>G mutation in mitochondrial DNA in blood derived from diabetic patients. Mol Diagnosis Therapy, 10 : 381-389 (2006).

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