title: Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26.
abstract: S-adenosylmethionine (SAM) is the predominant methyl group donor and has a large spectrum of target substrates. As such, it is essential for nearly all biological methylation reactions. SAM is synthesized by methionine adenosyltransferase from methionine and ATP in the cytoplasm and subsequently distributed throughout the different cellular compartments, including mitochondria, where methylation is mostly required for nucleic-acid modifications and respiratory-chain function. We report a syndrome in three families affected by reduced intra-mitochondrial methylation caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26. Clinical findings ranged from neonatal mortality resulting from respiratory insufficiency and hydrops to childhood acute episodes of cardiopulmonary failure and slowly progressive muscle weakness. We show that SLC25A26 mutations cause various mitochondrial defects, including those affecting RNA stability, protein modification, mitochondrial translation, and the biosynthesis of CoQ10 and lipoic acid.
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kishita
authors.affiliation: Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Pajak
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp 2650, Belgium.
authors.forename: Nikhita Ajit
authors.initials: NA
authors.lastname: Bolar
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Edoardo Orabona 4, 70125 Bari, Italy.
authors.forename: Carlo M T
authors.initials: CM
authors.lastname: Marobbio
authors.affiliation: Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Maffezzini
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Edoardo Orabona 4, 70125 Bari, Italy.
authors.forename: Daniela V
authors.initials: DV
authors.lastname: Miniero
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Edoardo Orabona 4, 70125 Bari, Italy; Department of Sciences, University of Basilicata, Via Ateneo Lucano 10, 85100 Potenza, Italy.
authors.forename: Magnus
authors.initials: M
authors.lastname: Monné
authors.affiliation: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohda
authors.affiliation: Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden; Science for Life Laboratory and Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Stranneheim
authors.affiliation: Department of Metabolism, Chiba Children's Hospital, 579-1 Heta-cho, Midori, Chiba 266-0007, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Murayama
authors.affiliation: Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Naess
authors.affiliation: Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Nicole
authors.initials: N
authors.lastname: Lesko
authors.affiliation: Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Helene
authors.initials: H
authors.lastname: Bruhn
authors.affiliation: Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Mourier
authors.affiliation: Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Wibom
authors.affiliation: Department of Pathology, Karolinska University Hospital, 171 77 Stockholm, Sweden.
authors.forename: Inger
authors.initials: I
authors.lastname: Nennesmo
authors.affiliation: Paola Children's Hospital, ZNA Middelheim, Antwerp 2650, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Jespers
authors.affiliation: Paola Children's Hospital, ZNA Middelheim, Antwerp 2650, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Govaert
authors.affiliation: Department of Pediatrics, Saitama Medical University, 38 Morohongo Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtake
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp 2650, Belgium.
authors.forename: Lut
authors.initials: L
authors.lastname: Van Laer
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp 2650, Belgium; Department of Genetics, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
authors.forename: Bart L
authors.initials: BL
authors.lastname: Loeys
authors.affiliation: Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden.
authors.forename: Christoph
authors.initials: C
authors.lastname: Freyer
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Edoardo Orabona 4, 70125 Bari, Italy. Electronic address: ferdinando.palmieri@uniba.it.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Palmieri
authors.affiliation: Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden. Electronic address: anna.wredenberg@ki.se.
authors.forename: Anna
authors.initials: A
authors.lastname: Wredenberg
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan; Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
authors.affiliation: Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden; Science for Life Laboratory and Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Wedell
mesh_terms: D000595:Amino Acid Sequence; D026905:Amino Acid Transport Systems / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002675:Child, Preschool; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D018908:Muscle Weakness / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011379:Prognosis; D020871:RNA Stability; D012436:S-Adenosylmethionine / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D008063:Thioctic Acid / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D026905:Amino Acid Transport Systems; D002135:Calcium-Binding Proteins; C487502:SLC25A26 protein, human; D014451:Ubiquinone; D008063:Thioctic Acid; D012436:S-Adenosylmethionine; C024989:coenzyme Q10
keywords: S-adenosylmethionine; SAM; SLC25A26; methylation; mitochondria; mitochondrial dysfunction