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

Nasca, Alessia; Rizza, Teresa; Doimo, Mara; Legati, Andrea; Ciolfi, Andrea; Diodato, Daria; Calderan, Cristina; Carrara, Gianfranco; Lamantea, Eleonora; Aiello, Chiara; Nottia, Michela Di; Niceta, Marcello; Lamperti, Costanza; Ardissone, Anna; Bianchi-Marzoli, Stefania; Iarossi, Giancarlo; Bertini, Enrico; Moroni, Isabella; Tartaglia, Marco; Salviati, Leonardo; Carrozzo, Rosalba; Ghezzi, Daniele

doi:10.1186/s13023-017-0641-1

Cited by 45 publications

(30 citation statements)

References 28 publications

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“…Similarly, areas of reduced immunoreactivity were observed using the TOMM20 antibody confirming impairment of the mitochondrial network distribution (right panel). These abnormalities were not detected in the muscle biopsy of a patient with biallelic mutations in OPA1 (last bottom row) already described (Nasca, Rizza et al, ). The plasma membrane is stained in red fluorescence with an antibody against dystrophin [Color figure can be viewed at wileyonlinelibrary.com]…”

Section: Resultsmentioning

confidence: 49%

“…Histochemistry of the muscle sample of a patient harboring compound heterozygous mutations in OPA1 (Nasca, Rizza et al, ) was studied and compared with those of DNM1L patients and showed no patchy staining abnormalities (Figure lowest panel). In addition, by Long Range PCR we also searched comparatively for multiple deletions in muscle samples and found multiple deletions only in the OPA1 mutated patient and not in the DNM1L patients (data not shown).…”

Section: Resultsmentioning

confidence: 99%

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Clinical-genetic features and peculiar muscle histopathology in infantileDNM1L-related mitochondrial epileptic encephalopathy

et al. 2019

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Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family, responsible for fission of mitochondria, and having a role in the division of peroxisomes, as well. DRP1 impairment is implicated in several neurological disorders and associated with either de novo dominant or compound heterozygous mutations. In five patients presenting Human Mutation. 2019;40:601-618.wileyonlinelibrary.com/journal/humu

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Section: Resultsmentioning

confidence: 49%

Section: Resultsmentioning

confidence: 99%

Clinical-genetic features and peculiar muscle histopathology in infantileDNM1L-related mitochondrial epileptic encephalopathy

et al. 2019

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“…Human COQ5 performs much better in yeast when its presequence is substituted by the yeast one (Nguyen et al., ). In the case of OPA1 , complementation was also achieved using hybrid constructs, which included the MTS and the transmembrane domain (Nasca et al., ; Nolli et al., ). In all these cases, these genes are considered orthologs of the yeast gene.…”

Section: Discussionmentioning

confidence: 99%

Mutations in COQ8B (ADCK4) found in patients with steroid-resistant nephrotic syndrome alter COQ8B function

et al. 2017

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Mutations in COQ8B cause steroid‐resistant nephrotic syndrome with variable neurological involvement. In yeast, COQ8 encodes a protein required for coenzyme Q (CoQ) biosynthesis, whose precise role is not clear. Humans harbor two paralog genes: COQ8A and COQ8B (previously termed ADCK3 and ADCK4). We have found that COQ8B is a mitochondrial matrix protein peripherally associated with the inner membrane. COQ8B can complement a ΔCOQ8 yeast strain when its mitochondrial targeting sequence (MTS) is replaced by a yeast MTS. This model was employed to validate COQ8B mutations, and to establish genotype–phenotype correlations. All mutations affected respiratory growth, but there was no correlation between mutation type and the severity of the phenotype. In fact, contrary to the case of COQ2, where residual CoQ biosynthesis correlates with clinical severity, patients harboring hypomorphic COQ8B alleles did not display a different phenotype compared with those with null mutations. These data also suggest that the system is redundant, and that other proteins (probably COQ8A) may partially compensate for the absence of COQ8B. Finally, a COQ8B polymorphism, present in 50% of the European population (NM_024876.3:c.521A > G, p.His174Arg), affects stability of the protein and could represent a risk factor for secondary CoQ deficiencies or for other complex traits.

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“…[14][15][16] Notably, compound heterozygous OPA1 mutations have been described in a few cases manifesting complex neurological involvement in addition to optic atrophy. 13,17,18 About 30% of DOA patients, however, do not carry OPA1 mutations. Heterozygous mutations in a second gene, associated with DOA and cataracts and/or deafness, affect the OPA3 gene, 19,20 known for the recessive Costeff syndrome (Online Mendelian Inheritance in Man database [OMIM] #258501).…”

Section: Introductionmentioning

confidence: 99%

ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy

Caporali

Magri

Legati

et al. 2020

Annals of Neurology

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Objective Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. Methods We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient‐derived fibroblasts. Results Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype‐modifier variants. All the DOA‐associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28‐associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA‐associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28‐associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission‐inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. Interpretation This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18–32

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

Cited by 45 publications

References 28 publications

Clinical-genetic features and peculiar muscle histopathology in infantileDNM1L-related mitochondrial epileptic encephalopathy

Clinical-genetic features and peculiar muscle histopathology in infantileDNM1L-related mitochondrial epileptic encephalopathy

Mutations in COQ8B (ADCK4) found in patients with steroid-resistant nephrotic syndrome alter COQ8B function

ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy

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