title: Biallelic Mutations in DNM1L are Associated with a Slowly Progressive Infantile Encephalopathy.
abstract: Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion, and mitochondrial dynamics is important for several cellular functions. DNM1L is the most important mediator of mitochondrial fission, with a role also in peroxisome division. Few reports of patients with genetic defects in DNM1L have been published, most of them describing de novo dominant mutations. We identified compound heterozygous DNM1L variants in two brothers presenting with an infantile slowly progressive neurological impairment. One variant was a frame-shift mutation, the other was a missense change, 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. In conclusion, we described a recessive disease caused by DNM1L mutations, with a clinical phenotype resembling mitochondrial disorders but without any biochemical features typical of these syndromes (lactic acidosis, respiratory chain complex deficiency) or indicating a peroxisomal disorder.
authors.affiliation: Unit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Nasca
authors.affiliation: Unit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Legati
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Baruffini
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nolli
authors.affiliation: Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
authors.affiliation: Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ardissone
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Goffrini
authors.affiliation: Unit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
mesh_terms: D000293:Adolescent; D000483:Alleles; D001927:Brain Diseases / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D018389:Codon, Nonsense; D034281:Dynamins; D016368:Frameshift Mutation; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008928:Mitochondria / Q000473:pathology*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D020675:Peroxisomes / Q000473:pathology
chemical_list: D018389:Codon, Nonsense; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: DNM1L; mitochondrial disorders; mitochondrial dynamics; mitochondrial fission; peroxisome