Validation of a MGM1/OPA1 chimeric gene for functional analysis in yeast of mutations associated with dominant optic atrophy

Nolli, Cecilia; Goffrini, P; Lazzaretti, Mirca; Zanna, Claudia; Vitale, Rita; Lodi, Tiziana; Baruffini, Enrico

doi:10.1016/j.mito.2015.10.002

Cited by 17 publications

(20 citation statements)

References 55 publications

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“…Our results suggest that missense mutations do not always lead to purely negative dominance. This is further supported by the introduction of the I382M missense mutation in a chimeric construct, which confirmed the haploinsufficient character of this mutation . We investigated other missense mutations to assess mitophagic and autophagic efficacy in DOA models.…”

Section: Discussionmentioning

confidence: 99%

“…However, the recent emergence of severe multisystemic disorders, associated with missense mutations predominantly clustered in the GTPase domain, suggests that dominant-negative or gain-of-function mutations may also play an important role in the pathological mechanism underlying DOA [6][7][8]. The mutated proteins arising from these missense mutations, which cause heterozygous amino acid substitutions, are hypothesized to inhibit the wild-type protein, thereby interfering with OPA1 functions [9]. This hypothetical mechanism is further supported by a study of GTPase mutants of the merozoite surface protein 1 paralog (MSP1P), an intermembrane-space dynaminrelated protein, in the wild-type yeast Schizosaccharomyces pombe [10].…”

Section: Introductionmentioning

confidence: 99%

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Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy

Kane

Alban

Desquiret-Dumas

et al. 2017

J Cellular Molecular Medi

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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 experimental mitochondrial injury. Our results indicate distinct alterations of mitochondrial physiology and turnover in cells with OPA1 mutations, suggesting that the level and profile of OPA1 may regulate the rate of mitophagy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy

Kane

Alban

Desquiret-Dumas

et al. 2017

J Cellular Molecular Medi

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“…Since mutations in several nuclear genes encoding for proteins involved in mitochondrial dynamics, such as MGM1 (the homologous gene of human OPA1 ) [Nolli et al., ; Sesaki et al., ], FZO1 (h MFN1 ) [Rapaport et al., ], and DNM1 itself [Bernhardt et al., ], affect mtDNA stability in yeast, we investigated whether the dnm1 mutations determine an increase of mtDNA extended mutability. We measured the frequency of petite , that is, clones which are unable to grow on an oxidative carbon source due to large deletions or lack of mtDNA.…”

Section: Acknowledgmentmentioning

confidence: 99%

Biallelic Mutations in DNM1L are Associated with a Slowly Progressive Infantile Encephalopathy

et al. 2016

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Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion, and mitochondrial dynamics is important for several cellular functions. DNM1L is the most important mediator of mitochondrial fission, with a role also in peroxisome division. Few reports of patients with genetic defects in DNM1L have been published, most of them describing de novo dominant mutations. We identified compound heterozygous DNM1L variants in two brothers presenting with an infantile slowly progressive neurological impairment. One variant was a frame‐shift mutation, the other was a missense change, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. In conclusion, we described a recessive disease caused by DNM1L mutations, with a clinical phenotype resembling mitochondrial disorders but without any biochemical features typical of these syndromes (lactic acidosis, respiratory chain complex deficiency) or indicating a peroxisomal disorder.

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“…Yeast lacking MGM1 cannot grow on non-fermentable carbon sources and develop a petite phenotype [24]. Human OPA1 per se cannot complement yeast MGM1 deletion mutants [24].…”

Section: Resultsmentioning

confidence: 99%

“…Human OPA1 per se cannot complement yeast MGM1 deletion mutants [24]. We therefore employed a hybrid gene comprised of the 5’ portion of MGM1 (encoding the targeting sequence and the transmembrane domain) and the 3’ portion of human OPA1 (from exon 6 to the stop codon).…”

Section: Resultsmentioning

confidence: 99%

Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations

Nasca

Rizza

Doimo

et al. 2017

Orphanet J Rare Dis

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BackgroundHeterozygous mutations in OPA1 are a common cause of autosomal dominant optic atrophy, sometimes associated with extra-ocular manifestations. Few cases harboring compound heterozygous OPA1 mutations have been described manifesting complex neurodegenerative disorders in addition to optic atrophy.ResultsWe report here three patients: one boy showing an early-onset mitochondrial disorder with hypotonia, ataxia and neuropathy that was severely progressive, leading to early death because of multiorgan failure; two unrelated sporadic girls manifesting a spastic ataxic syndrome associated with peripheral neuropathy and, only in one, optic atrophy. Using a targeted resequencing of 132 genes associated with mitochondrial disorders, in two probands we found compound heterozygous mutations in OPA1: in the first a 5 nucleotide deletion, causing a frameshift and insertion of a premature stop codon (p.Ser64Asnfs*7), and a missense change (p.Ile437Met), which has recently been reported to have clinical impact; in the second, a novel missense change (p.Val988Phe) co-occurred with the p.Ile437Met substitution. In the third patient a homozygous mutation, c.1180G > A (p.Ala394Thr) in OPA1 was detected by a trio-based whole exome sequencing approach. One of the patients presented also variants in mitochondrial DNA that may have contributed to the peculiar phenotype.The deleterious effect of the identified missense changes was experimentally validated in yeast model. OPA1 level was reduced in available patients’ biological samples, and a clearly fragmented mitochondrial network was observed in patients’ fibroblasts.ConclusionsThis report provides evidence that bi-allelic OPA1 mutations may lead to complex and severe multi-system recessive mitochondrial disorders, where optic atrophy might not represent the main feature.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0641-1) contains supplementary material, which is available to authorized users.

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Validation of a MGM1/OPA1 chimeric gene for functional analysis in yeast of mutations associated with dominant optic atrophy

Cited by 17 publications

References 55 publications

Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy

Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy

Biallelic Mutations in DNM1L are Associated with a Slowly Progressive Infantile Encephalopathy

Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations

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