2011
DOI: 10.1016/j.ymgme.2011.04.018
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Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations

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Cited by 74 publications
(52 citation statements)
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References 21 publications
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“…Their most striking observation is the identification of compound heterozygous OPA1 mutations in all four patients with the co-occurrence of a missense GTPase mutation and a truncative nonsense mutation. Interestingly, three of these families harboured the same missense GTPase OPA1 mutation (c.1146A>G, p.Ile382Met) that has been previously reported in another DOA+ family with compound heterozygous mutations (Schaaf et al , 2011). This specific pathogenic variant is clearly highly penetrant for the neurological ‘plus’ features and it does support our earlier observation that misssense GTPase OPA1 mutations seem to have a more potent deleterious impact, possibly via a dominant negative mechanism and increased mitochondrial DNA instability (Yu-Wai-Man et al , 2010; Yu-Wai-Man and Chinnery, 2012).…”
supporting
confidence: 60%
“…Their most striking observation is the identification of compound heterozygous OPA1 mutations in all four patients with the co-occurrence of a missense GTPase mutation and a truncative nonsense mutation. Interestingly, three of these families harboured the same missense GTPase OPA1 mutation (c.1146A>G, p.Ile382Met) that has been previously reported in another DOA+ family with compound heterozygous mutations (Schaaf et al , 2011). This specific pathogenic variant is clearly highly penetrant for the neurological ‘plus’ features and it does support our earlier observation that misssense GTPase OPA1 mutations seem to have a more potent deleterious impact, possibly via a dominant negative mechanism and increased mitochondrial DNA instability (Yu-Wai-Man et al , 2010; Yu-Wai-Man and Chinnery, 2012).…”
supporting
confidence: 60%
“…Since the homozygous mutants of Opa1 +/− mouse models are lethal during early embryogenesis, it was suspected that compound heterozygous early-onset cases of the Behr syndrome might associate a pathogenic variant with a milder hypomorphic variant. This was indeed found to be the case since seven unrelated DOA patients from France, Italy, Germany and the USA harbored the same variant, i.e., the p.Ile437Met change in the GTPase domain due to the c.1311ANG mutation in exon 12 (Bonifert et al, 2014;Bonneau et al, 2014;Carelli et al, 2015b;Schaaf et al, 2011). Although the p.Ile437Met mutation is asymptomatic by itself, when combined with a pathogenic variant it induced a severe pathological condition compatible with a recessive mode of inheritance.…”
Section: Diversity Of the Clinical Spectrum Of Opa1 Mutationsmentioning
confidence: 73%
“…Since 2011, a new early-onset OPA1-related clinical entity, distinct from those previously described, has been reported in a growing number of patients (Bonifert et al, 2014;Bonneau et al, 2014;Carelli et al, 2015b;Schaaf et al, 2011). This concerns a severe neurological syndrome associating early-onset optic neuropathy, occurring during the three first years of life, to spinocerebellar degeneration, pyramidal signs, peripheral neuropathy, gastrointestinal dysmobility and retarded development, a phenotype fully compatible with the Behr syndrome (Behr, 1909) …”
Section: Diversity Of the Clinical Spectrum Of Opa1 Mutationsmentioning
confidence: 99%
“…Nevertheless, the protein is expressed in all examined human tissues, explaining the accidental development of the so-called 'ADOA +' forms characterized by the association of the blindness with various neuromuscular disorders [17][18][19] or hearing loss [20,21]. The vulnerability of retinal ganglion cells and that of spiral ganglion cells in the inner ear [22] has been attributed to the impairment of ATP production as observed in fibroblasts [23,24] or skeletal muscle [25].…”
Section: Introductionmentioning
confidence: 99%