title: Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions.
abstract: The molecular diagnosis of mitochondrial disorders still remains elusive in a large proportion of patients, but advances in next generation sequencing are significantly improving our chances to detect mutations even in sporadic patients. Syndromes associated with mitochondrial DNA multiple deletions are caused by different molecular defects resulting in a wide spectrum of predominantly adult-onset clinical presentations, ranging from progressive external ophthalmoplegia to multi-systemic disorders of variable severity. The mutations underlying these conditions remain undisclosed in half of the affected subjects. We applied next-generation sequencing of known mitochondrial targets (MitoExome) to probands presenting with adult-onset mitochondrial myopathy and harbouring mitochondrial DNA multiple deletions in skeletal muscle. We identified autosomal recessive mutations in the DGUOK gene (encoding mitochondrial deoxyguanosine kinase), which has previously been associated with an infantile hepatocerebral form of mitochondrial DNA depletion. Mutations in DGUOK occurred in five independent subjects, representing 5.6% of our cohort of patients with mitochondrial DNA multiple deletions, and impaired both muscle DGUOK activity and protein stability. Clinical presentations were variable, including mitochondrial myopathy with or without progressive external ophthalmoplegia, recurrent rhabdomyolysis in a young female who had received a liver transplant at 9 months of age and adult-onset lower motor neuron syndrome with mild cognitive impairment. These findings reinforce the concept that mutations in genes involved in deoxyribonucleotide metabolism can cause diverse clinical phenotypes and suggest that DGUOK should be screened in patients harbouring mitochondrial DNA deletions in skeletal muscle.
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy. dario.ronchi@unimi.it
authors.forename: Dario
authors.initials: D
authors.lastname: Ronchi
authors.forename: Caterina
authors.initials: C
authors.lastname: Garone
authors.forename: Andreina
authors.initials: A
authors.lastname: Bordoni
authors.forename: Purificacion
authors.initials: P
authors.lastname: Gutierrez Rios
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Calvo
authors.forename: Michela
authors.initials: M
authors.lastname: Ripolone
authors.forename: Michela
authors.initials: M
authors.lastname: Ranieri
authors.forename: Mafalda
authors.initials: M
authors.lastname: Rizzuti
authors.forename: Luisa
authors.initials: L
authors.lastname: Villa
authors.forename: Francesca
authors.initials: F
authors.lastname: Magri
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Mootha
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiMauro
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
authors.forename: Monica
authors.initials: M
authors.lastname: Sciacco
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide
chemical_list: D004272:DNA, Mitochondrial; D017853:Phosphotransferases (Alcohol Group Acceptor); C019165:deoxyguanosine kinase