TY - JOUR
T1 - Clinical-genetic features and peculiar muscle histopathology in infantile DNM1L-related mitochondrial epileptic encephalopathy
AU - Verrigni, Daniela
AU - Di Nottia, Michela
AU - Ardissone, Anna
AU - Baruffini, Enrico
AU - Nasca, Alessia
AU - Legati, Andrea
AU - Bellacchio, Emanuele
AU - Fagiolari, Gigliola
AU - Martinelli, Diego
AU - Martinelli, Daniela
AU - Fusco, Lucia
AU - Battaglia, Domenica Immacolata
AU - Trani, Giulia
AU - Versienti, Gianmarco
AU - Marchet, Silvia
AU - Torraco, Alessandra
AU - Rizza, Teresa
AU - Verardo, Margherita
AU - D'Amico, Adele
AU - Diodato, Daria
AU - Moroni, Isabella
AU - Lamperti, Costanza
AU - Petrini, Stefania
AU - Moggio, Maurizio
AU - Goffrini, Paola
AU - Ghezzi, Daniele
AU - Ghezzi, Daniele Maria
AU - Carrozzo, Rosalba
AU - Bertini, Enrico
AU - Bertini, Enrico Silvio
PY - 2019
Y1 - 2019
N2 - 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 with severe epileptic encephalopathy, we identified five de novo dominant DNM1L variants, 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. Moreover, a very peculiar finding in our cohort of patients was the presence, in muscle biopsy, of core like areas with oxidative enzyme alterations, suggesting an abnormal distribution of mitochondria in the muscle tissue.
AB - 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 with severe epileptic encephalopathy, we identified five de novo dominant DNM1L variants, 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. Moreover, a very peculiar finding in our cohort of patients was the presence, in muscle biopsy, of core like areas with oxidative enzyme alterations, suggesting an abnormal distribution of mitochondria in the muscle tissue.
KW - Biomarkers
KW - Brain
KW - DNA Mutational Analysis
KW - DNM1L
KW - Dynamins
KW - Fibroblasts
KW - Genetic Association Studies
KW - Genetic Predisposition to Disease
KW - Humans
KW - Magnetic Resonance Imaging
KW - Mitochondrial Encephalomyopathies
KW - Models, Biological
KW - Muscles
KW - Mutation
KW - Protein Conformation
KW - Structure-Activity Relationship
KW - epileptic encephalopathy
KW - mitochondrial disorders
KW - mitochondrial dynamics
KW - mitochondrial fission
KW - muscle biopsy
KW - Biomarkers
KW - Brain
KW - DNA Mutational Analysis
KW - DNM1L
KW - Dynamins
KW - Fibroblasts
KW - Genetic Association Studies
KW - Genetic Predisposition to Disease
KW - Humans
KW - Magnetic Resonance Imaging
KW - Mitochondrial Encephalomyopathies
KW - Models, Biological
KW - Muscles
KW - Mutation
KW - Protein Conformation
KW - Structure-Activity Relationship
KW - epileptic encephalopathy
KW - mitochondrial disorders
KW - mitochondrial dynamics
KW - mitochondrial fission
KW - muscle biopsy
UR - http://hdl.handle.net/10807/161742
U2 - 10.1002/humu.23729
DO - 10.1002/humu.23729
M3 - Article
SN - 1059-7794
VL - 40
SP - 601
EP - 618
JO - Human Mutation
JF - Human Mutation
ER -