Patrizia Amati-bonneau - Academia.edu (original) (raw)

Papers by Patrizia Amati-bonneau

Molecular Neurodegeneration, 2021

Inherited optic neuropathies are the most common mitochondrial diseases, leading to neurodegenera... more Inherited optic neuropathies are the most common mitochondrial diseases, leading to neurodegeneration involving the irreversible loss of retinal ganglion cells, optic nerve degeneration and central visual loss. Importantly, properly regulated mitochondrial dynamics are critical for maintaining cellular homeostasis, and are further regulated by MIEF1 (mitochondrial elongation factor 1) which encodes for MID51 (mitochondrial dynamics protein 51), an outer mitochondrial membrane protein that acts as an adaptor protein to regulate mitochondrial fission. However, dominant mutations in MIEF1 have not been previously linked to any human disease. Using targeted sequencing of genes involved in mitochondrial dynamics, we report the first heterozygous variants in MIEF1 linked to disease, which cause an unusual form of late-onset progressive optic neuropathy characterized by the initial loss of peripheral visual fields. Pathogenic MIEF1 variants linked to optic neuropathy do not disrupt MID51’s...

European Journal of Ophthalmology, 2011

European Journal of Human Genetics, 2018

Inherited optic neuropathies can be caused by mitochondrial DNA (mtDNA) variants as in Leber here... more Inherited optic neuropathies can be caused by mitochondrial DNA (mtDNA) variants as in Leber hereditary optic neuropathy (Table 1) or by variants in nuclear-encoded genes (Table 2).

Orphanet Journal of Rare Diseases, 2018

Backrground: Evaluation of the efficacy of oral cyclosporine A as a prophylactic agent in prevent... more Backrground: Evaluation of the efficacy of oral cyclosporine A as a prophylactic agent in preventing second-eye involvement in Leber's hereditary optic neuropathy (LHON) in a prospective, open-label, non-randomized, multicenter pilot study. Only LHON patients aged 18 years or more, with confirmed primary mitochondrial DNA mutations and strictly unilateral optic neuropathy occurring within 6 months prior to enrolment, were included in the study. All these patients, receiving treatment with oral cyclosporine (Neoral®, Novartis) at 2.5 mg/kg/day, were examined at three-month intervals for a year. The primary endpoint was the best corrected visual acuity in the unaffected eye; the secondary endpoints were the best corrected visual acuity in the first eye affected, the mean visual field defect on automated perimetry, the thickness of the perifoveal retinal ganglion cell inner plexiform layer, and the thickness of the peripapillary retinal nerve fiber layer in both eyes. Results: Among the 24 patients referred to our institution with genetically confirmed LHON, between July 2011 and April 2014, only five patients, four males and one female, fulfilled the inclusion criteria. Age at enrolment ranged from 19 to 42 years (mean: 27.2 years; median: 26 years), four patients harbored the m.11778G > A pathogenic variant, and one the m.14484 T > C pathogenic variant. The time-interval between the onset of symptoms and inclusion in the study ranged from 7 to 17 weeks (mean: 11.8 weeks; median: 9 weeks). Despite treatment with oral cyclosporine A, all patients eventually experienced bilateral eye involvement, occurring within 11-65 weeks after the initiation of treatment. Over the study time period, the average best corrected visual acuity worsened in the first eye affected; by the end of the study, both eyes were equally affected. Conclusions: Oral cyclosporine, at 2.5 mg/kg/day, did not prevent second-eye involvement in patients with strictly unilateral Leber's hereditary optic neuropathy.

Brain : a journal of neurology, 2018

Journal of cellular and molecular medicine, Jan 4, 2017

Optic Atrophy 1 (OPA1) gene mutations cause diseases ranging from isolated dominant optic atrophy... more Optic Atrophy 1 (OPA1) gene mutations cause diseases ranging from isolated dominant optic atrophy (DOA) to various multisystemic disorders. OPA1, a large GTPase belonging to the dynamin family, is involved in mitochondrial network dynamics. The majority of OPA1 mutations encodes truncated forms of the protein and causes DOA through haploinsufficiency, whereas missense OPA1 mutations are predicted to cause disease through deleterious dominant-negative mechanisms. We used 3D imaging and biochemical analysis to explore autophagy and mitophagy in fibroblasts from seven patients harbouring OPA1 mutations. We report new genotype-phenotype correlations between various types of OPA1 mutation and mitophagy. Fibroblasts bearing dominant-negative OPA1 mutations showed increased autophagy and mitophagy in response to uncoupled oxidative phosphorylation. In contrast, OPA1 haploinsufficiency was correlated with a substantial reduction in mitochondrial turnover and autophagy, unless subjected to e...

Investigative Opthalmology & Visual Science, 2017

E, et al. Targeted metabolomics reveals early dominant optic atrophy signature in optic nerves of... more E, et al. Targeted metabolomics reveals early dominant optic atrophy signature in optic nerves of Opa1 delTTAG/þ mice.

Journal of Medical Genetics, 2016

Background Non-syndromic hereditary optic neuropathy (HON) has been ascribed to mutations in mito... more Background Non-syndromic hereditary optic neuropathy (HON) has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. The objective of the present study was to identify the molecular cause of non-syndromic LHON-like disease in siblings born to non-consanguineous parents of French origin. Methods We used a combination of genetic analysis (gene mapping and whole-exome sequencing) in a multiplex family of non-syndromic HON and of functional analyses in patient-derived cultured skin fibroblasts and the yeast Yarrowia lipolytica. Results We identified compound heterozygote NDUFS2 disease-causing mutations (p.Tyr53Cys; p.Tyr308Cys). Studies using patient-derived cultured skin fibroblasts revealed mildly decreased NDUFS2 and complex I abundance but apparently normal respiratory chain activity. In the yeast Y. lipolytica ortholog NUCM, the mutations resulted in absence of complex I and moderate reduction in nicotinamide adenine dinucleotide-ubiquinone oxidoreductase activity, respectively. Conclusions Biallelism for NDUFS2 mutations causing severe complex I deficiency has been previously reported to cause Leigh syndrome with optic neuropathy. Our results are consistent with the view that compound heterozygosity for severe and hypomorphic NDUFS2 mutations can cause nonsyndromic HON. This observation suggests a direct correlation between the severity of NDUFS2 mutations and that of the disease and further support that there exist a genetic overlap between non-syndromic and syndromic HON due to defective mitochondrial function.

Molecular vision, 2009

Autosomal dominant optic atrophy (ADOA, OMIM 165500), an inherited optic neuropathy that leads to... more Autosomal dominant optic atrophy (ADOA, OMIM 165500), an inherited optic neuropathy that leads to retinal ganglion cell degeneration and reduced visual acuity during the early decades of life, is mainly associated with mutations in the OPA1 gene. Here we report a novel ADOA phenotype associated with a new pathogenic OPA1 gene mutation. The patient, a 62-year-old woman, was referred for acute, painless, and severe visual loss in her right eye. Acute visual loss in her left eye occurred a year after initial presentation. MRI confirmed the diagnosis of isolated atrophic bilateral optic neuropathy. We performed DNA sequencing of the entire coding sequence and the exon/intron junctions of the OPA1 gene, and we searched for the mitochondrial DNA mutations responsible for Leber hereditary optic atrophy by sequencing entirely mitochondrial DNA. Mitochondrial respiratory chain complex activity and mitochondrial morphology were investigated in skin fibroblasts from the patient and controls. W...

Journal of medical genetics, 2014

Inherited optic neuropathy has been ascribed to mutations in mitochondrial fusion/fission dynamic... more Inherited optic neuropathy has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. We used exome sequencing in order to identify the gene responsible for isolated or syndromic optic atrophy in five patients from three independent families. We found homozygous or compound heterozygous missense and frameshift mutations in the gene encoding mitochondrial aconitase (ACO2), a tricarboxylic acid cycle enzyme, catalysing interconversion of citrate into isocitrate. Unlike wild type ACO2, all mutant ACO2 proteins failed to complement the respiratory growth of a yeast aco1-deletion strain. Retrospective studies using patient-derived cultured skin fibroblasts revealed various degrees of deficiency in ACO2 activity, but also in ACO1 cytosolic activity. Our study shows that autosomal rece...

médecine/sciences, 2010

DRP1, dynamin-related protein 1) ont ensuite été impliqués dans une forme axonale de la maladie d... more DRP1, dynamin-related protein 1) ont ensuite été impliqués dans une forme axonale de la maladie de Charcot-Marie-Tooth (CMT) [3, 36] (➜) et un syndrome neurologique néonatal sévère [4]. Enfin, un quatrième gène codant la protéine GDAP1 (ganglioside-induced differentiation-associated protein 1) impliquée dans le contrôle de la fission mitochondriale, fut associé à deux autres formes de CMT [5, 6]. Ces pathologies neurologiques, qui semblent liées à une altération de la plasticité mitochondriale, définissent une nouvelle classe de maladies mitochondriales, en marge de celles dues à un déficit primitif de la chaîne respiratoire. Les mécanismes physiopathologiques mis en jeu sont fort complexes puisque la plasticité mitochondriale semble se situer au carrefour d'un ensemble de processus interdépendants : contrôle de qualité de l'organite-biogenèse, mitophagie, maintien de l'ADN mitochondrial-, fonctions bioénergétiques, distribution cellulaire et interaction avec les autres composants cellulaires, flux calciques, intégrations des voies de signalisation cellulaire et apoptose (➜).

Brain : a journal of neurology, 2014

This 14-year-old male was the second child born to nonconsanguineous parents. His mother had been... more This 14-year-old male was the second child born to nonconsanguineous parents. His mother had been diagnosed with

The FASEB Journal, 2011

Charcot-Marie-Tooth disease type 2A (CMT2A) is an autosomal dominant axonal form of peripheral ne... more Charcot-Marie-Tooth disease type 2A (CMT2A) is an autosomal dominant axonal form of peripheral neuropathy caused by mutations in the mitofusin 2 gene (MFN2), which encodes a mitochondrial outer membrane protein that promotes mitochondrial fusion. Emerging evidence also points to a role of MFN2 in the regulation of mitochondrial metabolism. To examine whether mitochondrial dysfunction is a feature of CMT2A, we used a transgenic mouse model expressing in neurons a mutated R94Q form of human MFN2 shown to induce a CMT2A phenotype. Oxygraphic and enzymatic measurements both revealed a combined defect of mitochondrial complexes II and V (40 and 30% decrease, respectively) in the brain of Tg-R94 mice, leading to a drastic decrease of ATP synthesis. These deficiencies were reversed by the mitochondrial ATP-sensitive potassium channel (mK ATP) inhibitor 5-hydroxydecanoate. Conversely, in controls and wild-type human MFN2 mice, the mK ATP activator diazoxide mimicked the deficiency observed with the R94Q mutation. The physical links between complexes II and V, previously proposed as part of mK ATP , were reinforced in Tg-R94Q mice. Our results show that the R94Q MFN2 mutation induces a combined defect of complexes II and V linked to the opening of mK ATP , which could participate in the pathophysiology of the disease.

PLoS ONE, 2012

Background: Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disorde... more Background: Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disorder, which in over 90% of cases is due to one of three primary mitochondrial DNA (mtDNA) point mutations (m.11778G.A, m.3460G.A and m.14484T.C, respectively in MT-ND4, MT-ND1 and MT-ND6 genes). However, the spectrum of mtDNA mutations causing the remaining 10% of cases is only partially and often poorly defined. Methodology/Principal Findings: In order to improve such a list of pathological variants, we completely sequenced the mitochondrial genomes of suspected LHON patients from Italy, France and Germany, lacking the three primary common mutations. Phylogenetic and conservation analyses were performed. Sixteen mitochondrial genomes were found to harbor at least one of the following nine rare LHON pathogenic mutations in genes MT-ND1 (m.3700G.A/p.A132T, m.3733G.A-C/ p.E143K-Q, m.4171C.A/p.L289M), MT-ND4L (m.10663T.C/p.V65A) and MT-ND6 (m.14459G.A/p.A72V, m.14495A.G/ p.M64I, m.14482C.A/p.L60S, and m.14568C.T/p.G36S). Phylogenetic analyses revealed that these substitutions were due to independent events on different haplogroups, whereas interspecies comparisons showed that they affected conserved amino acid residues or domains in the ND subunit genes of complex I. Conclusions/Significance: Our findings indicate that these nine substitutions are all primary LHON mutations. Therefore, despite their relative low frequency, they should be routinely tested for in all LHON patients lacking the three common mutations. Moreover, our sequence analysis confirms the major role of haplogroups J1c and J2b (over 35% in our probands versus 6% in the general population of Western Europe) and other putative synergistic mtDNA variants in LHON expression.

Orphanet Journal of Rare Diseases, 2012

Definition of the disease: Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition character... more Definition of the disease: Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain. Epidemiology: The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world. Clinical description: DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts. Aetiology: Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis. Diagnosis: Patients are usually diagnosed during their early childhood, because of bilateral, mild, otherwise unexplained visual loss related to optic discs pallor or atrophy, and typically occurring in the context of a family history of DOA. Optical Coherence Tomography further discloses non-specific thinning of retinal nerve fiber layer, but a normal morphology of the photoreceptors layers. Abnormal visual evoked potentials and pattern ERG may also reflect the dysfunction of the RGCs and their axons. Molecular diagnosis is provided by the identification of a mutation in the OPA1 gene (75% of DOA patients) or in the OPA3 gene (1% of patients). Prognosis: Visual loss in DOA may progress during puberty until adulthood, with very slow subsequent chronic progression in most of the cases. On the opposite, in DOA patients with associated extra-ocular features, the visual loss may be more severe over time. Management: To date, there is no preventative or curative treatment in DOA; severely visually impaired patients may benefit from low vision aids. Genetic counseling is commonly offered and patients are advised to avoid alcohol and tobacco consumption, as well as the use of medications that may interfere with mitochondrial metabolism. Gene and pharmacological therapies for DOA are currently under investigation.

Ophthalmic Epidemiology, 2013

Journal of Neurology, Neurosurgery & Psychiatry, 2010

ABSTRACT OPA1 codes for a mitochondrial fusion protein found on the inner mitochondrial membrane.... more ABSTRACT OPA1 codes for a mitochondrial fusion protein found on the inner mitochondrial membrane. Mutations in OPA1 are the most common cause of autosomal dominant optic atrophy (DOA), and until recently, this was thought to be a pure ocular disorder. By studying 104 patients from 45 independent families we have defined the clinical spectrum of this new multisystem mitochondrial disease, which we have called DOA+. We show that extra-ocular neurological complications affect ∼20%, and include sensorineural deafness in childhood, followed by ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia in the very late stages. We have also identified novel clinical presentations mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness resembling "Harding's disease", first described in patients with Leber hereditary optic neuropathy. We show that the risk of DOA+ is greatest in patients with mis-sense mutations, particularly those affecting the GTPase region of the protein, and that secondary mitochondrial DNA defects are likely to be responsible for the extra-ocular features. Individuals with DOA+ phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimise the detection and management of neurological disability in a group of patients with already significant visual impairment.

Journal of Medical Genetics, 2004

Journal of Cellular Physiology, 2007

Autosomal dominant optic atrophy (ADOA 1 ; MIM#165500) is the most common form of inherited optic... more Autosomal dominant optic atrophy (ADOA 1 ; MIM#165500) is the most common form of inherited optic neuropathy with a frequency of 1:12 000 to 1:50 000 (1,2). This disease is characterized by the insidious onset of visual impairment in early childhood with moderate to severe loss of visual acuity, temporal optic disc pallor, abnormalities of color vision and caecocentral visual field