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Concurrent AFG3L2 and SPG7 mutations associated with syndromic parkinsonism and optic atrophy with aberrant OPA1 processing and mitochondrial network fragmentation
Author(s) -
Magri Stefania,
Fracasso Valentina,
Plumari Massimo,
Alfei Enrico,
Ghezzi Daniele,
Gellera Cinzia,
Rusmini Paola,
Poletti Angelo,
Bella Daniela,
Elia Antonio E.,
Pantaleoni Chiara,
Taroni Franco
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23658
Subject(s) - biology , spinocerebellar ataxia , genetics , hereditary spastic paraplegia , parkinsonism , mitochondrial fusion , mitochondrial dna , phenotype , pathology , gene , medicine , disease
Mitochondrial dynamics and quality control are crucial for neuronal survival and their perturbation is a major cause of neurodegeneration. m ‐AAA complex is an ATP‐dependent metalloprotease located in the inner mitochondrial membrane and involved in protein quality control. Mutations in the m ‐AAA subunits AFG3L2 and paraplegin are associated with autosomal dominant spinocerebellar ataxia (SCA28) and autosomal recessive hereditary spastic paraplegia (SPG7), respectively. We report a novel m ‐AAA‐associated phenotype characterized by early‐onset optic atrophy with spastic ataxia and L‐dopa‐responsive parkinsonism. The proband carried a de novo AFG3L2 heterozygous mutation (p.R468C) along with a heterozygous maternally inherited intragenic deletion of SPG7 . Functional analysis in yeast demonstrated the pathogenic role of AFG3L2 p.R468C mutation shedding light on its pathogenic mechanism. Analysis of patient's fibroblasts showed an abnormal processing pattern of OPA1, a dynamin‐related protein essential for mitochondrial fusion and responsible for most cases of hereditary optic atrophy. Consistently, assessment of mitochondrial morphology revealed a severe fragmentation of the mitochondrial network, not observed in SCA28 and SPG7 patients’ cells. This case suggests that coincidental mutations in both components of the mitochondrial m ‐AAA protease may result in a complex phenotype and reveals a crucial role for OPA1 processing in the pathogenesis of neurodegenerative disease caused by m ‐AAA defects.