TY - JOUR
T1 - ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy
AU - Caporali, Leonardo
AU - Magri, Stefania
AU - Legati, Andrea
AU - Del Dotto, Valentina
AU - Tagliavini, Francesca
AU - Balistreri, Francesca
AU - Nasca, Alessia
AU - La Morgia, Chiara
AU - Carbonelli, Michele
AU - Valentino, Maria L.
AU - Lamantea, Eleonora
AU - Baratta, Silvia
AU - Schöls, Ludger
AU - Schüle, Rebecca
AU - Barboni, Piero
AU - Cascavilla, Maria L.
AU - Maresca, Alessandra
AU - Capristo, Mariantonietta
AU - Ardissone, Anna
AU - Pareyson, Davide
AU - Cammarata, Gabriella
AU - Melzi, Lisa
AU - Zeviani, Massimo
AU - Peverelli, Lorenzo
AU - Lamperti, Costanza
AU - Marzoli, Stefania B.
AU - Fang, Mingyan
AU - Synofzik, Matthis
AU - Ghezzi, Daniele
AU - Carelli, Valerio
AU - Taroni, Franco
N1 - Ricercatore distaccato presso IRCCS a seguito Convenzione esclusiva con Università di Bologna (La Morgia Chiara, Carelli Valerio, Valentino Maria Lucia)
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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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U2 - 10.1002/ana.25723
DO - 10.1002/ana.25723
M3 - Article
C2 - 32219868
AN - SCOPUS:85083678159
VL - 88
SP - 18
EP - 32
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
IS - 1
ER -